Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.
The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.
A genotoxicological technique for measuring DNA damage in an individual cell using single-cell gel electrophoresis. Cell DNA fragments assume a "comet with tail" formation on electrophoresis and are detected with an image analysis system. Alkaline assay conditions facilitate sensitive detection of single-strand damage.
A group of PROTEIN-SERINE-THREONINE KINASES which activate critical signaling cascades in double strand breaks, APOPTOSIS, and GENOTOXIC STRESS such as ionizing ultraviolet A light, thereby acting as a DNA damage sensor. These proteins play a role in a wide range of signaling mechanisms in cell cycle control.
Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS.
That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-UV or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-UV or abiotic or extravital rays) are viricidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants.
A nucleoside consisting of the base guanine and the sugar deoxyribose.
Enzyme activated in response to DNA DAMAGE involved in cell cycle arrest. The gene is located on the long (q) arm of chromosome 22 at position 12.1. In humans it is encoded by the CHEK2 gene.
Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.
Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.
Interruptions in the sugar-phosphate backbone of DNA, across both strands adjacently.
A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.
A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi).
The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.
Proteins that are normally involved in holding cellular growth in check. Deficiencies or abnormalities in these proteins may lead to unregulated cell growth and tumor development.
Penetrating, high-energy electromagnetic radiation emitted from atomic nuclei during NUCLEAR DECAY. The range of wavelengths of emitted radiation is between 0.1 - 100 pm which overlaps the shorter, more energetic hard X-RAYS wavelengths. The distinction between gamma rays and X-rays is based on their radiation source.
One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).
An alkylating agent in cancer therapy that may also act as a mutagen by interfering with and causing damage to DNA.
Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each.
Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes.
Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.
An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional.
The period of the CELL CYCLE following DNA synthesis (S PHASE) and preceding M PHASE (cell division phase). The CHROMOSOMES are tetraploid in this point.
The process by which a DNA molecule is duplicated.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
A cell line derived from cultured tumor cells.
Enzymes that are involved in the reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule, which contained damaged regions.
The relationship between the dose of administered radiation and the response of the organism or tissue to the radiation.
The products of chemical reactions that result in the addition of extraneous chemical groups to DNA.
Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of signal transduction and gene expression, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS.
The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.
Established cell cultures that have the potential to propagate indefinitely.
A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials.
Interruptions in the sugar-phosphate backbone of DNA.
The ability of some cells or tissues to survive lethal doses of IONIZING RADIATION. Tolerance depends on the species, cell type, and physical and chemical variables, including RADIATION-PROTECTIVE AGENTS and RADIATION-SENSITIZING AGENTS.
A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.
Enzymes that catalyze the transfer of multiple ADP-RIBOSE groups from nicotinamide-adenine dinucleotide (NAD) onto protein targets, thus building up a linear or branched homopolymer of repeating ADP-ribose units i.e., POLY ADENOSINE DIPHOSPHATE RIBOSE.
Genes that code for proteins that regulate the CELL DIVISION CYCLE. These genes form a regulatory network that culminates in the onset of MITOSIS by activating the p34cdc2 protein (PROTEIN P34CDC2).
Regulatory signaling systems that control the progression through the CELL CYCLE. They ensure that the cell has completed, in the correct order and without mistakes, all the processes required to replicate the GENOME and CYTOPLASM, and divide them equally between two daughter cells. If cells sense they have not completed these processes or that the environment does not have the nutrients and growth hormones in place to proceed, then the cells are restrained (or "arrested") until the processes are completed and growth conditions are suitable.
Interruptions in one of the strands of the sugar-phosphate backbone of double-stranded DNA.
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
A Rec A recombinase found in eukaryotes. Rad51 is involved in DNA REPAIR of double-strand breaks.
A family of DNA repair enzymes that recognize damaged nucleotide bases and remove them by hydrolyzing the N-glycosidic bond that attaches them to the sugar backbone of the DNA molecule. The process called BASE EXCISION REPAIR can be completed by a DNA-(APURINIC OR APYRIMIDINIC SITE) LYASE which excises the remaining RIBOSE sugar from the DNA.
The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.
Phase of the CELL CYCLE following G1 and preceding G2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome.
Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.
The phosphoprotein encoded by the BRCA1 gene (GENE, BRCA1). In normal cells the BRCA1 protein is localized in the nucleus, whereas in the majority of breast cancer cell lines and in malignant pleural effusions from breast cancer patients, it is localized mainly in the cytoplasm. (Science 1995;270(5237):713,789-91)
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.
A type of CELL NUCLEUS division by means of which the two daughter nuclei normally receive identical complements of the number of CHROMOSOMES of the somatic cells of the species.
The decrease in the cell's ability to proliferate with the passing of time. Each cell is programmed for a certain number of cell divisions and at the end of that time proliferation halts. The cell enters a quiescent state after which it experiences CELL DEATH via the process of APOPTOSIS.
Induction and quantitative measurement of chromosomal damage leading to the formation of micronuclei (MICRONUCLEI, CHROMOSOME-DEFECTIVE) in cells which have been exposed to genotoxic agents or IONIZING RADIATION.
A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.
Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase.
Naturally occurring or synthetic substances that inhibit or retard the oxidation of a substance to which it is added. They counteract the harmful and damaging effects of oxidation in animal tissues.
A serine-threonine protein kinase that, when activated by DNA, phosphorylates several DNA-binding protein substrates including the TUMOR SUPPRESSOR PROTEIN P53 and a variety of TRANSCRIPTION FACTORS.
CELL CYCLE regulatory signaling systems that are triggered by DNA DAMAGE or lack of nutrients during G2 PHASE. When triggered they restrain cells transitioning from G2 phase to M PHASE.
Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.
The material of CHROMOSOMES. It is a complex of DNA; HISTONES; and nonhistone proteins (CHROMOSOMAL PROTEINS, NON-HISTONE) found within the nucleus of a cell.
Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.
Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard X-rays are the higher energy, shorter wavelength X-rays. Soft x-rays or Grenz rays are less energetic and longer in wavelength. The short wavelength end of the X-ray spectrum overlaps the GAMMA RAYS wavelength range. The distinction between gamma rays and X-rays is based on their radiation source.
Elements of limited time intervals, contributing to particular results or situations.
A single-stranded DNA-binding protein that is found in EUKARYOTIC CELLS. It is required for DNA REPLICATION; DNA REPAIR; and GENETIC RECOMBINATION.
Repair of DNA DAMAGE by exchange of DNA between matching sequences, usually between the allelic DNA (ALLELES) of sister chromatids.
Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
Proteins that catalyze the unwinding of duplex DNA during replication by binding cooperatively to single-stranded regions of DNA or to short regions of duplex DNA that are undergoing transient opening. In addition DNA helicases are DNA-dependent ATPases that harness the free energy of ATP hydrolysis to translocate DNA strands.
A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471).
A polynucleotide formed from the ADP-RIBOSE moiety of nicotinamide-adenine dinucleotide (NAD) by POLY(ADP-RIBOSE) POLYMERASES.
The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability.
Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
An error-prone mechanism or set of functions for repairing damaged microbial DNA. SOS functions (a concept reputedly derived from the SOS of the international distress signal) are involved in DNA repair and mutagenesis, in cell division inhibition, in recovery of normal physiological conditions after DNA repair, and possibly in cell death when DNA damage is extensive.
An E3 UBIQUITIN LIGASE that interacts with and inhibits TUMOR SUPPRESSOR PROTEIN P53. Its ability to ubiquitinate p53 is regulated by TUMOR SUPPRESSOR PROTEIN P14ARF.
Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.
Dimers found in DNA chains damaged by ULTRAVIOLET RAYS. They consist of two adjacent PYRIMIDINE NUCLEOTIDES, usually THYMINE nucleotides, in which the pyrimidine residues are covalently joined by a cyclobutane ring. These dimers block DNA REPLICATION.
A DNA repair enzyme that is an N-glycosyl hydrolase with specificity for DNA-containing ring-opened N(7)-methylguanine residues.
An antineoplastic antibiotic produced by Streptomyces caespitosus. It is one of the bi- or tri-functional ALKYLATING AGENTS causing cross-linking of DNA and inhibition of DNA synthesis.
Human COLORECTAL CARCINOMA cell line.
Defective nuclei produced during the TELOPHASE of MITOSIS or MEIOSIS by lagging CHROMOSOMES or chromosome fragments derived from spontaneous or experimentally induced chromosomal structural changes.
The act of ligating UBIQUITINS to PROTEINS to form ubiquitin-protein ligase complexes to label proteins for transport to the PROTEASOME ENDOPEPTIDASE COMPLEX where proteolysis occurs.
A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.
A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs.
Compounds that inhibit cell production of DNA or RNA.
The repair of DOUBLE-STRAND DNA BREAKS by rejoining the broken ends of DNA to each other directly.
Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.
Tests of chemical substances and physical agents for mutagenic potential. They include microbial, insect, mammalian cell, and whole animal tests.
The relationship between the dose of an administered drug and the response of the organism to the drug.
A ZINC FINGER MOTIF protein that recognizes and interacts with damaged DNA. It is a DNA-binding protein that plays an essential role in NUCLEOTIDE EXCISION REPAIR. Mutations in this protein are associated with the most severe form of XERODERMA PIGMENTOSUM.
White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each), or NATURAL KILLER CELLS.
Deoxyribonucleic acid that makes up the genetic material of fungi.
An autosomal recessive inherited disorder characterized by choreoathetosis beginning in childhood, progressive CEREBELLAR ATAXIA; TELANGIECTASIS of CONJUNCTIVA and SKIN; DYSARTHRIA; B- and T-cell immunodeficiency, and RADIOSENSITIVITY to IONIZING RADIATION. Affected individuals are prone to recurrent sinobronchopulmonary infections, lymphoreticular neoplasms, and other malignancies. Serum ALPHA-FETOPROTEINS are usually elevated. (Menkes, Textbook of Child Neurology, 5th ed, p688) The gene for this disorder (ATM) encodes a cell cycle checkpoint protein kinase and has been mapped to chromosome 11 (11q22-q23).
Electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (OXIDATION-REDUCTION).
A group of enzymes catalyzing the endonucleolytic cleavage of DNA. They include members of EC 3.1.21.-, EC 3.1.22.-, EC 3.1.23.- (DNA RESTRICTION ENZYMES), EC 3.1.24.- (DNA RESTRICTION ENZYMES), and EC 3.1.25.-.
A subclass of dual specificity phosphatases that play a role in the progression of the CELL CYCLE. They dephosphorylate and activate CYCLIN-DEPENDENT KINASES.
Nuclear antigen with a role in DNA synthesis, DNA repair, and cell cycle progression. PCNA is required for the coordinated synthesis of both leading and lagging strands at the replication fork during DNA replication. PCNA expression correlates with the proliferation activity of several malignant and non-malignant cell types.
Immunologically detectable substances found in the CELL NUCLEUS.
Enzymes that catalyze the hydrolysis of the internal bonds and thereby the formation of polynucleotides or oligonucleotides from ribo- or deoxyribonucleotide chains. EC 3.1.-.
A gene silencing phenomenon whereby specific dsRNAs (RNA, DOUBLE-STRANDED) trigger the degradation of homologous mRNA (RNA, MESSENGER). The specific dsRNAs are processed into SMALL INTERFERING RNA (siRNA) which serves as a guide for cleavage of the homologous mRNA in the RNA-INDUCED SILENCING COMPLEX. DNA METHYLATION may also be triggered during this process.
Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.
Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included.
An exchange of DNA between matching or similar sequences.
Tumor suppressor genes located on the short arm of human chromosome 17 and coding for the phosphoprotein p53.
Proteins obtained from the species Schizosaccharomyces pombe. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.
A condition characterized by long-standing brain dysfunction or damage, usually of three months duration or longer. Potential etiologies include BRAIN INFARCTION; certain NEURODEGENERATIVE DISORDERS; CRANIOCEREBRAL TRAUMA; ANOXIA, BRAIN; ENCEPHALITIS; certain NEUROTOXICITY SYNDROMES; metabolic disorders (see BRAIN DISEASES, METABOLIC); and other conditions.
Splitting the DNA into shorter pieces by endonucleolytic DNA CLEAVAGE at multiple sites. It includes the internucleosomal DNA fragmentation, which along with chromatin condensation, are considered to be the hallmarks of APOPTOSIS.
Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor.
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
Substances that inhibit or prevent the proliferation of NEOPLASMS.
7,8,8a,9a-Tetrahydrobenzo(10,11)chryseno (3,4-b)oxirene-7,8-diol. A benzopyrene derivative with carcinogenic and mutagenic activity.
All of the processes involved in increasing CELL NUMBER including CELL DIVISION.
A genus of ascomycetous fungi of the family Schizosaccharomycetaceae, order Schizosaccharomycetales.
The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.
A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.
A family of enzymes that catalyze the exonucleolytic cleavage of DNA. It includes members of the class EC 3.1.11 that produce 5'-phosphomonoesters as cleavage products.
Rate of energy dissipation along the path of charged particles. In radiobiology and health physics, exposure is measured in kiloelectron volts per micrometer of tissue (keV/micrometer T).
A highly conserved 76-amino acid peptide universally found in eukaryotic cells that functions as a marker for intracellular PROTEIN TRANSPORT and degradation. Ubiquitin becomes activated through a series of complicated steps and forms an isopeptide bond to lysine residues of specific proteins within the cell. These "ubiquitinated" proteins can be recognized and degraded by proteosomes or be transported to specific compartments within the cell.
A diverse class of enzymes that interact with UBIQUITIN-CONJUGATING ENZYMES and ubiquitination-specific protein substrates. Each member of this enzyme group has its own distinct specificity for a substrate and ubiquitin-conjugating enzyme. Ubiquitin-protein ligases exist as both monomeric proteins multiprotein complexes.
Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.
Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake.
Nucleoproteins, which in contrast to HISTONES, are acid insoluble. They are involved in chromosomal functions; e.g. they bind selectively to DNA, stimulate transcription resulting in tissue-specific RNA synthesis and undergo specific changes in response to various hormones or phytomitogens.
Mature male germ cells derived from SPERMATIDS. As spermatids move toward the lumen of the SEMINIFEROUS TUBULES, they undergo extensive structural changes including the loss of cytoplasm, condensation of CHROMATIN into the SPERM HEAD, formation of the ACROSOME cap, the SPERM MIDPIECE and the SPERM TAIL that provides motility.
A potent mutagen and carcinogen. This compound and its metabolite 4-HYDROXYAMINOQUINOLINE-1-OXIDE bind to nucleic acids. It inactivates bacteria but not bacteriophage.
An in situ method for detecting areas of DNA which are nicked during APOPTOSIS. Terminal deoxynucleotidyl transferase is used to add labeled dUTP, in a template-independent manner, to the 3 prime OH ends of either single- or double-stranded DNA. The terminal deoxynucleotidyl transferase nick end labeling, or TUNEL, assay labels apoptosis on a single-cell level, making it more sensitive than agarose gel electrophoresis for analysis of DNA FRAGMENTATION.
An exchange of segments between the sister chromatids of a chromosome, either between the sister chromatids of a meiotic tetrad or between the sister chromatids of a duplicated somatic chromosome. Its frequency is increased by ultraviolet and ionizing radiation and other mutagenic agents and is particularly high in BLOOM SYNDROME.
A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.
An enediyne that alkylates DNA and RNA like MITOMYCIN does, so it is cytotoxic.
A single chain of deoxyribonucleotides that occurs in some bacteria and viruses. It usually exists as a covalently closed circle.
Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS.
A family of structurally-related DNA helicases that play an essential role in the maintenance of genome integrity. RecQ helicases were originally discovered in E COLI and are highly conserved across both prokaryotic and eukaryotic organisms. Genetic mutations that result in loss of RecQ helicase activity gives rise to disorders that are associated with CANCER predisposition and premature aging.
A class of enzymes involved in the hydrolysis of the N-glycosidic bond of nitrogen-linked sugars.
A ubiquitously expressed telomere-binding protein that is present at TELOMERES throughout the cell cycle. It is a suppressor of telomere elongation and may be involved in stabilization of telomere length. It is structurally different from TELOMERIC REPEAT BINDING PROTEIN 1 in that it contains basic N-terminal amino acid residues.
DNA present in neoplastic tissue.
A DNA repair enzyme that catalyses the excision of ribose residues at apurinic and apyrimidinic DNA sites that can result from the action of DNA GLYCOSYLASES. The enzyme catalyzes a beta-elimination reaction in which the C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. This enzyme was previously listed under EC 3.1.25.2.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
The mechanisms effecting establishment, maintenance, and modification of that specific physical conformation of CHROMATIN determining the transcriptional accessibility or inaccessibility of the DNA.
Agents that reduce the frequency or rate of spontaneous or induced mutations independently of the mechanism involved.
Cell regulatory signaling system that controls progression through S PHASE and stabilizes the replication forks during conditions that could affect the fidelity of DNA REPLICATION, such as DNA DAMAGE or depletion of nucleotide pools.
The period of the CELL CYCLE preceding DNA REPLICATION in S PHASE. Subphases of G1 include "competence" (to respond to growth factors), G1a (entry into G1), G1b (progression), and G1c (assembly). Progression through the G1 subphases is effected by limiting growth factors, nutrients, or inhibitors.
An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.
Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated.
A rare, pigmentary, and atrophic autosomal recessive disease. It is manifested as an extreme photosensitivity to ULTRAVIOLET RAYS as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA.
Abnormal number or structure of chromosomes. Chromosome aberrations may result in CHROMOSOME DISORDERS.
An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1.
Microscopy of specimens stained with fluorescent dye (usually fluorescein isothiocyanate) or of naturally fluorescent materials, which emit light when exposed to ultraviolet or blue light. Immunofluorescence microscopy utilizes antibodies that are labeled with fluorescent dye.
Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.
DNA-dependent DNA polymerases found in bacteria, animal and plant cells. During the replication process, these enzymes catalyze the addition of deoxyribonucleotide residues to the end of a DNA strand in the presence of DNA as template-primer. They also possess exonuclease activity and therefore function in DNA repair.
Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.
Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.
An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA TOPOISOMERASES, TYPE I. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity.
Substances that influence the course of a chemical reaction by ready combination with free radicals. Among other effects, this combining activity protects pancreatic islets against damage by cytokines and prevents myocardial and pulmonary perfusion injuries.
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
Chemical substances, produced by microorganisms, inhibiting or preventing the proliferation of neoplasms.
New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.
Drugs used to protect against ionizing radiation. They are usually of interest for use in radiation therapy but have been considered for other, e.g. military, purposes.
A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides.
A Fanconi anemia complementation group protein that undergoes mono-ubiquitination by FANCL PROTEIN in response to DNA DAMAGE. Also, in response to IONIZING RADIATION it can undergo PHOSPHORYLATION by ataxia telangiectasia mutated protein. Modified FANCD2 interacts with BRCA2 PROTEIN in a stable complex with CHROMATIN, and it is involved in DNA REPAIR by homologous RECOMBINATION.
An oxidoreductase that catalyzes the conversion of HYDROGEN PEROXIDE to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in ACATALASIA.
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.
Compounds that inhibit the activity of DNA TOPOISOMERASE I.
An increased tendency to acquire CHROMOSOME ABERRATIONS when various processes involved in chromosome replication, repair, or segregation are dysfunctional.
Formation of an acetyl derivative. (Stedman, 25th ed)
Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.
Phosphoprotein with protein kinase activity that functions in the G2/M phase transition of the CELL CYCLE. It is the catalytic subunit of the MATURATION-PROMOTING FACTOR and complexes with both CYCLIN A and CYCLIN B in mammalian cells. The maximal activity of cyclin-dependent kinase 1 is achieved when it is fully dephosphorylated.
Changes in the organism associated with senescence, occurring at an accelerated rate.
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
A nitrosoguanidine derivative with potent mutagenic and carcinogenic properties.
Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed)
A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
DNA TOPOISOMERASES that catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. DNA Topoisomerases, Type I enzymes reduce the topological stress in the DNA structure by relaxing the superhelical turns and knotted rings in the DNA helix.
The artificial induction of GENE SILENCING by the use of RNA INTERFERENCE to reduce the expression of a specific gene. It includes the use of DOUBLE-STRANDED RNA, such as SMALL INTERFERING RNA and RNA containing HAIRPIN LOOP SEQUENCE, and ANTI-SENSE OLIGONUCLEOTIDES.
Proteins found in any species of fungus.
A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.
A DNA-binding protein that mediates DNA REPAIR of double strand breaks, and HOMOLOGOUS RECOMBINATION.
A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.
Transport proteins that carry specific substances in the blood or across cell membranes.
Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.
Congenital disorder affecting all bone marrow elements, resulting in ANEMIA; LEUKOPENIA; and THROMBOPENIA, and associated with cardiac, renal, and limb malformations as well as dermal pigmentary changes. Spontaneous CHROMOSOME BREAKAGE is a feature of this disease along with predisposition to LEUKEMIA. There are at least 7 complementation groups in Fanconi anemia: FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL. (from Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227650, August 20, 2004)
Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.
Compounds that inhibit the activity of DNA TOPOISOMERASES.
Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS.
A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.
Histochemical localization of immunoreactive substances using labeled antibodies as reagents.
Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells.
A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.
The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.
Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc.
A family of recombinases initially identified in BACTERIA. They catalyze the ATP-driven exchange of DNA strands in GENETIC RECOMBINATION. The product of the reaction consists of a duplex and a displaced single-stranded loop, which has the shape of the letter D and is therefore called a D-loop structure.
The outer covering of the body that protects it from the environment. It is composed of the DERMIS and the EPIDERMIS.
The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group.
A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.
An E2F transcription factor that interacts directly with RETINOBLASTOMA PROTEIN and CYCLIN A and activates GENETIC TRANSCRIPTION required for CELL CYCLE entry and DNA synthesis. E2F1 is involved in DNA REPAIR and APOPTOSIS.
Macromolecular complexes formed from the association of defined protein subunits.

Long-range oxidative damage to DNA: effects of distance and sequence. (1/17364)

INTRODUCTION: Oxidative damage to DNA in vivo can lead to mutations and cancer. DNA damage and repair studies have not yet revealed whether permanent oxidative lesions are generated by charges migrating over long distances. Both photoexcited *Rh(III) and ground-state Ru(III) intercalators were previously shown to oxidize guanine bases from a remote site in oligonucleotide duplexes by DNA-mediated electron transfer. Here we examine much longer charge-transport distances and explore the sensitivity of the reaction to intervening sequences. RESULTS: Oxidative damage was examined in a series of DNA duplexes containing a pendant intercalating photooxidant. These studies revealed a shallow dependence on distance and no dependence on the phasing orientation of the oxidant relative to the site of damage, 5'-GG-3'. The intervening DNA sequence has a significant effect on the yield of guanine oxidation, however. Oxidation through multiple 5'-TA-3' steps is substantially diminished compared to through other base steps. We observed intraduplex guanine oxidation by tethered *Rh(III) and Ru(III) over a distance of 200 A. The distribution of oxidized guanine varied as a function of temperature between 5 and 35 degrees C, with an increase in the proportion of long-range damage (> 100 A) occurring at higher temperatures. CONCLUSIONS: Guanines are oxidized as a result of DNA-mediated charge transport over significant distances (e.g. 200 A). Although long-range charge transfer is dependent on distance, it appears to be modulated by intervening sequence and sequence-dependent dynamics. These discoveries hold important implications with respect to DNA damage in vivo.  (+info)

Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. (2/17364)

This report demonstrates that Gadd45, a p53-responsive stress protein, can facilitate topoisomerase relaxing and cleavage activity in the presence of core histones. A correlation between reduced expression of Gadd45 and increased resistance to topoisomerase I and topoisomerase II inhibitors in a variety of human cell lines was also found. Gadd45 could potentially mediate this effect by destabilizing histone-DNA interactions since it was found to interact directly with the four core histones. To evaluate this possibility, we investigated the effect of Gadd45 on preassembled mononucleosomes. Our data indicate that Gadd45 directly associates with mononucleosomes that have been altered by histone acetylation or UV radiation. This interaction resulted in increased DNase I accessibility on hyperacetylated mononucleosomes and substantial reduction of T4 endonuclease V accessibility to cyclobutane pyrimidine dimers on UV-irradiated mononucleosomes but not on naked DNA. Both histone acetylation and UV radiation are thought to destabilize the nucleosomal structure. Hence, these results imply that Gadd45 can recognize an altered chromatin state and modulate DNA accessibility to cellular proteins.  (+info)

The Saccharomyces cerevisiae ETH1 gene, an inducible homolog of exonuclease III that provides resistance to DNA-damaging agents and limits spontaneous mutagenesis. (3/17364)

The recently sequenced Saccharomyces cerevisiae genome was searched for a gene with homology to the gene encoding the major human AP endonuclease, a component of the highly conserved DNA base excision repair pathway. An open reading frame was found to encode a putative protein (34% identical to the Schizosaccharomyces pombe eth1(+) [open reading frame SPBC3D6.10] gene product) with a 347-residue segment homologous to the exonuclease III family of AP endonucleases. Synthesis of mRNA from ETH1 in wild-type cells was induced sixfold relative to that in untreated cells after exposure to the alkylating agent methyl methanesulfonate (MMS). To investigate the function of ETH1, deletions of the open reading frame were made in a wild-type strain and a strain deficient in the known yeast AP endonuclease encoded by APN1. eth1 strains were not more sensitive to killing by MMS, hydrogen peroxide, or phleomycin D1, whereas apn1 strains were approximately 3-fold more sensitive to MMS and approximately 10-fold more sensitive to hydrogen peroxide than was the wild type. Double-mutant strains (apn1 eth1) were approximately 15-fold more sensitive to MMS and approximately 2- to 3-fold more sensitive to hydrogen peroxide and phleomycin D1 than were apn1 strains. Elimination of ETH1 in apn1 strains also increased spontaneous mutation rates 9- or 31-fold compared to the wild type as determined by reversion to adenine or lysine prototrophy, respectively. Transformation of apn1 eth1 cells with an expression vector containing ETH1 reversed the hypersensitivity to MMS and limited the rate of spontaneous mutagenesis. Expression of ETH1 in a dut-1 xthA3 Escherichia coli strain demonstrated that the gene product functionally complements the missing AP endonuclease activity. Thus, in apn1 cells where the major AP endonuclease activity is missing, ETH1 offers an alternate capacity for repair of spontaneous or induced damage to DNA that is normally repaired by Apn1 protein.  (+info)

Impaired translesion synthesis in xeroderma pigmentosum variant extracts. (4/17364)

Xeroderma pigmentosum variant (XPV) cells are characterized by a cellular defect in the ability to synthesize intact daughter DNA strands on damaged templates. Molecular mechanisms that facilitate replication fork progression on damaged DNA in normal cells are not well defined. In this study, we used single-stranded plasmid molecules containing a single N-2-acetylaminofluorene (AAF) adduct to analyze translesion synthesis (TLS) catalyzed by extracts of either normal or XPV primary skin fibroblasts. In one of the substrates, the single AAF adduct was located at the 3' end of a run of three guanines that was previously shown to induce deletion of one G by a slippage mechanism. Primer extension reactions performed by normal cellular extracts from four different individuals produced the same distinct pattern of TLS, with over 80% of the products resulting from the elongation of a slipped intermediate and the remaining 20% resulting from a nonslipped intermediate. In contrast, with cellular extracts from five different XPV patients, the TLS reaction was strongly reduced, yielding only low amounts of TLS via the nonslipped intermediate. With our second substrate, in which the AAF adduct was located at the first G in the run, thus preventing slippage from occurring, we confirmed that normal extracts were able to perform TLS 10-fold more efficiently than XPV extracts. These data demonstrate unequivocally that the defect in XPV cells resides in translesion synthesis independently of the slippage process.  (+info)

Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene. (5/17364)

The xeroderma pigmentosum group G (XP-G) gene (XPG) encodes a structure-specific DNA endonuclease that functions in nucleotide excision repair (NER). XP-G patients show various symptoms, ranging from mild cutaneous abnormalities to severe dermatological impairments. In some cases, patients exhibit growth failure and life-shortening and neurological dysfunctions, which are characteristics of Cockayne syndrome (CS). The known XPG protein function as the 3' nuclease in NER, however, cannot explain the development of CS in certain XP-G patients. To gain an insight into the functions of the XPG protein, we have generated and examined mice lacking xpg (the mouse counterpart of the human XPG gene) alleles. The xpg-deficient mice exhibited postnatal growth failure and underwent premature death. Since XPA-deficient mice, which are totally defective in NER, do not show such symptoms, our data indicate that XPG performs an additional function(s) besides its role in NER. Our in vitro studies showed that primary embryonic fibroblasts isolated from the xpg-deficient mice underwent premature senescence and exhibited the early onset of immortalization and accumulation of p53.  (+info)

Analysis of genomic integrity and p53-dependent G1 checkpoint in telomerase-induced extended-life-span human fibroblasts. (6/17364)

Life span determination in normal human cells may be regulated by nucleoprotein structures called telomeres, the physical ends of eukaryotic chromosomes. Telomeres have been shown to be essential for chromosome stability and function and to shorten with each cell division in normal human cells in culture and with age in vivo. Reversal of telomere shortening by the forced expression of telomerase in normal cells has been shown to elongate telomeres and extend the replicative life span (H. Vaziri and S. Benchimol, Curr. Biol. 8:279-282, 1998; A. G. Bodnar et al., Science 279:349-352, 1998). Extension of the life span as a consequence of the functional inactivation of p53 is frequently associated with loss of genomic stability. Analysis of telomerase-induced extended-life-span fibroblast (TIELF) cells by G banding and spectral karyotyping indicated that forced extension of the life span by telomerase led to the transient formation of aberrant structures, which were subsequently resolved in higher passages. However, the p53-dependent G1 checkpoint was intact as assessed by functional activation of p53 protein in response to ionizing radiation and subsequent p53-mediated induction of p21(Waf1/Cip1/Sdi1). TIELF cells were not tumorigenic and had a normal DNA strand break rejoining activity and normal radiosensitivity in response to ionizing radiation.  (+info)

Phosphorylation of the DNA repair protein APE/REF-1 by CKII affects redox regulation of AP-1. (7/17364)

The DNA repair protein apurinic endonuclease (APE/Ref-1) exerts several physiological functions such as cleavage of apurinic/apyrimidinic sites and redox regulation of the transcription factor AP-1, whose activation is part of the cellular response to DNA damaging treatments. Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1. Inhibition of CKII mediated phosphorylation of APE/Ref-1 blocked mutagen-stimulated increase in AP-1 binding. It also abrogated the induction of c-Jun protein and rendered cells more sensitive to induced DNA damage. Thus, phosphorylation of APE/Ref-1 appears to be involved in regulating the different physiological activities of the enzyme. CKII mediated phosphorylation of APE/Ref-1 and concomitant increase in AP-1 binding activity appears to be a novel mechanism of cellular stress response, forcing transcription of AP-1 target gene(s) the product(s) of which may exert protective function.  (+info)

Differential regulation of p21waf-1/cip-1 and Mdm2 by etoposide: etoposide inhibits the p53-Mdm2 autoregulatory feedback loop. (8/17364)

The Mdm2 protein is frequently overexpressed in human non-seminomatous germ cell tumours and transitional carcinoma of the bladder where it may contribute to tolerance of wtp53. Mdm2 forms an autoregulatory feedback loop with p53; the Mdm2 gene is responsive to transactivation by p53 and once synthesized the Mdm2 protein terminates the p53 response. We show here that the topoisomerase poison etoposide, like ultra violet irradiation, inhibits Mdm2 synthesis. Cytotoxic concentrations of etoposide (IC90 for > 3 h) result in inhibition of Mdm2 induction at both the RNA and protein level. Rapid apoptosis ensues. Global transcription is not inhibited: p21waf-1/cip1 and GADD45 expression increase in a dose dependent manner. Inhibition of Mdm2 synthesis depends on the continuous presence of etoposide, suggesting the DNA damage may prevent transcription. Downregulation of Mdm2 transcript occurs in cells expressing HPV16-E6 suggesting that inhibition of Mdm2 transcription is p53-independent. When cells are -treated with a pulse (1 h) of etoposide and reincubated in drug free medium, Mdm2 synthesis commences immediately after damage is repaired (3 h) and the p53 response is attenuated. Induction of apoptosis and loss of clonogenicity are 3-5-fold lower under pulse treatment conditions. This is the first observation of inhibition of Mdm2 transcription following treatment with topoisomerase (topo II) poisons, a feature that may be useful in tumour types where p53 is tolerated by overexpression of Mdm2.  (+info)

Endogenous oxidative DNA damage is caused by multiple endogenous and exogenous factors. It is not completely known whether coronary angiography has an effect on DNA damage. The aim of this study was to investigate whether coronary angiography causes oxidative DNA damage. Fifty-four patients who underwent elective coronary angiography for diagnostic purpose were enrolled to the study. For each subject, the frequency of oxidative DNA damage was analyzed by using the comet assay, which is a sensitive biomarker of DNA damage, before and after diagnostic procedures. A highly significant increase of DNA damage mean score was observed in all patients after the coronary angiography procedure (p < 0.001). No significant associations were found between the change in oxidative DNA damage and dose of contrast media and radiation exposure time. A significant correlation was observed between the change of DNA damage and age, hyperlipidemia, hypertension, smoking, Gensini score index, and vitamin B,2 (r = ...
The cellular response to DNA damage is critical for maintenance of genomic integrity and inhibition of tumorigenesis. Mutations or aberrant expression of the E3 ubiquitin ligase EDD have been observed in a number of carcinomas and we recently reported that EDD modulates activity of the DNA damage checkpoint kinase, CHK2. Here, we demonstrate that EDD is necessary for G(1)/S and intra S phase DNA damage checkpoint activation and for the maintenance of G(2)/M arrest after double strand DNA breaks. Defective checkpoint activation in EDD-depleted cells led to radio-resistant DNA synthesis, premature entry into mitosis, accumulation of polyploid cells, and cell death via mitotic catastrophe. In addition to decreased CHK2 activation in EDD-depleted cells, the expression of several key cell cycle mediators including Cdc25A/C and E2F1 was altered, suggesting that these checkpoint defects may be both CHK2-dependent and -independent. These data support a role for EDD in the maintenance of genomic stability,
DNA damage plays a causal role in numerous human pathologies including cancer, premature aging and chronic inflammatory conditions. In response to genotoxic insults, the DNA damage response (DDR) orchestrates DNA damage checkpoint activation and facilitates the removal of DNA lesions. The DDR can also arouse the immune system by for example inducing the expression of antimicrobial peptides as well as ligands for receptors found on immune cells. The activation of immune signalling is triggered by different components of the DDR including DNA damage sensors, transducer kinases, and effectors. In this review, we describe recent advances on the understanding of the role of DDR in activating immune signalling. We highlight evidence gained into (i) which molecular and cellular pathways of DDR activate immune signalling, (ii) how DNA damage drives chronic inflammation, and (iii) how chronic inflammation causes DNA damage and pathology in humans.
Protein synthesis and degradation are posttranscriptional pathways used by cells to regulate protein levels. We have developed a systems biology approach to identify targets of posttranscriptional regulation and we have employed this system in Saccharomyces cerevisiae to study the DNA damage response. We present evidence that 50% to 75% of the transcripts induced by alkylation damage are regulated posttranscriptionally. Significantly, we demonstrate that two transcriptionally-induced DNA damage response genes, RNR1 and RNR4, fail to show soluble protein level increases after DNA damage. To determine one of the associated mechanisms of posttranscriptional regulation, we tracked ribonucleotide reductase 1 (Rnr1) protein levels during the DNA damage response. We show that RNR1 is actively translated after damage and that a large fraction of the corresponding Rnr1 protein is packaged into a membrane-bound structure and transported to the vacuole for degradation, with these last two steps dependent ...
One function of cell cycle checkpoints is to integrate cell cycle progression with DNA replication and repair. Therefore, the integrity of these checkpoints is considered essential in maintaining genetic stability. Mutations in checkpoint components may lead to aberrant cell cycle progression and, in the presence of DNA damage, may lead to subsequent genetic instability. DNA damage triggers a variety of cellular responses, including activation of DNA damage response pathways. In fission yeast, genetic evidence pointed to a model in which five checkpoint Rad proteins, Rad1, Rad9, Rad17, Rad26, and Hus1, sense DNA alterations and then cooperate to send a signal through Rad3 (1) . Rad3 can also function in the absence of several of these Rad genes, suggesting that Rad3 may interact with other proteins involved in the DNA damage response (4) .. In S. pombe the cell cycle checkpoint gene Rad1 is required to ensure that mitosis does not occur in the presence of DNA damage (8 , 9) . X-Spy1 was ...
Lans H, Lindvall JM, Thijssen K, Karambelas AE, Cupac D, Fensgård O, Jansen G, Hoeijmakers JH, Nilsen H, Vermeulen W Cell Death Differ. 20 (12) 1709-1718 [2013-12-00; online 2013-09-10] Human-nucleotide-excision repair (NER) deficiency leads to different developmental and segmental progeroid symptoms of which the pathogenesis is only partially understood. To understand the biological impact of accumulating spontaneous DNA damage, we studied the phenotypic consequences of DNA-repair deficiency in Caenorhabditis elegans. We find that DNA damage accumulation does not decrease the adult life span of post-mitotic tissue. Surprisingly, loss of functional ERCC-1/XPF even further extends the life span of long-lived daf-2 mutants, likely through an adaptive activation of stress signaling. Contrariwise, NER deficiency leads to a striking transgenerational decline in replicative capacity and viability of proliferating cells. DNA damage accumulation induces severe, stochastic impairment of development and ...
Proteins involved in the DNA damage response accumulate as microscopically-visible nuclear foci on the chromatin flanking DNA double-strand breaks (DSBs). As growth of ionizing radiation (IR)-induced foci amplifies the ATM-dependent DNA damage signal, the formation of discrete foci plays a crucial role in cell cycle checkpoint activation, especially in cells exposed to lower doses of IR. However, there is no quantitative parameter for the foci which considers both the number and their size. Therefore, we have developed a novel parameter for DNA damage signal based on the image analysis of the foci and quantified the amount of the signal sufficient for G2 arrest. The parameter that we have developed here was designated as SOID. SOID is an abbreviation of Sum Of Integrated Density, which represents the sum of fluorescence of each focus within one nucleus. The SOID was calculated for individual nucleus as the sum of (area (total pixel numbers) of each focus) x (mean fluorescence intensity per pixel of each
Daily exposure to environmental agents (reactive oxygen species, methylating agents, UV light, and other ionizing radiation) and normal physiological processes (replication and recombination) all damage DNA. Cells must repair DNA damage to prevent mutations from propagating and accumulating, and to maintain genome integrity and stability. The ATM and ATR genes often initiate the DNA damage response, activating signal transduction pathways that arrest the cell cycle and increase the expression of DNA repair genes. Enzymes involved in base-excision, nucleotide excision, mismatch, double-strand break, and other DNA repair processes all respond in a pre- and post-transcriptionally regulated fashion to DNA damage. Incomplete DNA repair normally activates cell death pathways such as apoptosis. Cells unable to sense and repair DNA damage may continue to grow and divide, eventually causing cellular dysfunction and death, a hallmark of diseases such as neurological defects and infertility. However, ...
DNA damage (alkaline filter elution) and sister chromatid exchange (SCE) frequencies were measured in lymphocytes of 39 welders and 39 controls. The welders showed a significantly higher rate of DNA single-strand breakages and significantly elevated SCE values. These results are not in accordance with those of a former study in which only DNA-protein cross-links were measured. The different results may be explained on the basis of different exposure levels for chromium(VI) and nickel. Both methods are not specific but sensitive enough to measure genotoxic damage after occupational exposure to chromium(VI) and nickel in the range of threshold values for the workplace on a collective basis. Additionally, the results indicate that DNA single-strand breakage and DNA-protein cross-links show different increases depending on the exposure levels for chromium and nickel. ...
TY - JOUR. T1 - Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration. AU - Tuxworth , Richard AU - Taylor, Matthew AU - Anduaga, Ane Martin AU - Hussien-Ali, Al. AU - Chatzimatthaiou, Sotiroula AU - Longland, Joanne AU - Thompson, Adam. AU - Almutiri, Sharif AU - Alifragis, Pavlos. AU - Kyriacou, Charalambos AU - Kysela, Boris AU - Ahmed, Zubair PY - 2019/7/2. Y1 - 2019/7/2. N2 - DNA double-strand breaks are a feature of many acute and long-term neurological disorders, including neurodegeneration, following neurotrauma and after stroke. Persistent activation of the DNA damage response in response to double-strand breaks contributes to neural dysfunction and pathology as it can force post-mitotic neurons to re-enter the cell cycle leading to senescence or apoptosis. Mature, non-dividing neurons may tolerate low levels of DNA damage, in which case muting the DNA damage response might be neuroprotective. Here, we show that attenuating the ...
Faithful duplication and segregation of undamaged DNA is critical to the survival of all organisms and prevention of oncogenesis in multicellular organisms. To ensure inheritance of intact DNA, cells rely on checkpoints. Checkpoints alter cellular processes in the presence of DNA damage preventing cell cycle transitions until replication is completed or DNA damage is repaired. Several checkpoints are specific to S-phase. The S-M replication checkpoint prevents mitosis in the presence of unreplicated DNA. Rather than outright halting replication, the S-phase DNA damage checkpoint slows replication in response to DNA damage. This checkpoint utilizes two general mechanisms to slow replication. First, this checkpoint prevents origin firing thus limiting the number of replication forks traversing the genome in the presence of damaged DNA. Second, this checkpoint slows the progression of the replication forks. Inhibition of origin firing in response to DNA damage is well established, however when this thesis
DNA houses the blueprint that dictates how an organism will develop. However, DNA features numerous reactive sites that can be attacked by chemicals and radiation, resulting in DNA damage and possibly mutations. Chemical products and other environmental toxins must be tested for genetic abnormalities due to exposure. Traditional DNA damage detection can be tedious, time-consuming, and cost prohibitive. Electrochemical methods to detect DNA damage offer remedies to these drawbacks. Simple and sensitive DNA hybridization sensors are widely used for DNA detection and studying biochemical processes at specific DNA sequences. An electrochemical DNA hybridization sensor designed to detect DNA damage at hotspot TP53 gene sequences resulting from bioactivated benzo[a]pyrene (BP) will be discussed. TP53 codes for the p53 protein, and mutations at the studied genetic sequence have been shown to be prevalent in many different cancers. Double stranded DNA 21-mers were absorbed on gold electrodes followed by ...
In light of the studies discussed above (and below), we suggest a revised model of the DNA damage response (Fig. 2). In this model, DNA damage is initially detected by specific repair factor(s) that have an affinity for specific types of primary DNA lesion. In some cases, the lesion may be relatively easy to repair so that the DNA damage becomes rapidly reversed after initial detection. Under these circumstances, repair would occur sufficiently quickly to prevent recognition by components of the Mec1p/Tel1p signaling network and initiation of the DNA damage response. Consistent with this, it has been reported that HO-induced DSBs only trigger Rad53p activation when repair of these lesions is prevented by inactivation of HR (50). Similarly, even though hydrogen peroxide-induced DNA base damage does not trigger Rad53p activation during G1 or G2 in wild-type yeast cells, decreasing the efficiency of BER allows Rad53p activation in response to this type of DNA damage (51). Furthermore, when ...
As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates, that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage. In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response. It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage. Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair. Plays also a role in base excision repair (BER) probably through interaction with ...
The vast majority of DNA damage affects the primary structure of the double helix in which the bases are chemically modified. These modifications can in turn disrupt the molecules regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. DNA damages that are naturally occurring due to metabolism and its byproducts occur at a high rate in the body. Most of these damages to DNA from naturally occurring metabolism are repaired. However, there may remain some DNA damage despite the action of repair processes. These remaining DNA damages accumulate in the tissues.. There are a number of sources that contribute to DNA damage. DNA damage can be subdivided into two main types, either endogenous damage from naturally occurring metabolic processes and/or exogenous damage caused by external agents.. Endogenous damage caused by metabolic byproducts (naturally occurring):. ...
The cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and appears to selectively affect the expression of DNA damage response (DDR) and mRNA processing genes. Yet, the mechanism(s) by which it achieves this selectivity remains unclear. Using a highly selective CDK12/13 inhibitor, THZ531, and nascent RNA sequencing, we show that CDK12 inhibition results in gene length-dependent elongation defects, leading to premature cleavage and polyadenylation (PCPA) as well as loss of expression of long (,45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlated with an increased proportion of intronic polyadenylation sites, a feature that was especially prominent among DDR genes. Finally, phosphoproteomic analysis indicated that pre-mRNA processing factors, including those involved in PCPA, are direct phosphotargets of CDKs 12 and 13. These results support a model ...
Tumors exhibit genomic instability that arises from environmental and endogenous sources of DNA damage. To prevent the propagation of unstable genomes, the DNA damage response DDR pathway is activated during each cell cycle to ensure accurate DNA replication, repair of damaged DNA and apoptosis of heavily damaged cells. Thus, the DDR pathway functions as a barrier to cancer. DDR activation has been observed in precancerous lesions and has led to the idea that unresolved problems accumulated during DNA replication promote tumorigenesis. Such damaged sites halt the progression of DNA polymerases and cause replication stress that activates the DDR. Repair and restart of damaged replication forks requires the concerted effort of several DNA repair proteins, including the tumor suppressor BRCA1 breast cancer 1 and other DDR proteins that have yet to be characterized. I hypothesized that multiple DDR pathways prevent the accumulation of replication stress observed in precancerous and cancerous lesions of the
The COMET test measures sperm DNA damage (fragmentation). Sperm DNA can be damaged when sperm are made, breaking the DNA into smaller fragments. Men with high levels of sperm DNA damage are less likely to get their partner pregnant and have increased risk of miscarriage (1-5). Even if your sperm count is normal, the sperm may not be of good quality, and therefore sperm DNA damage can reduce the chance of you/partner having a baby (1-5).. Why should I get tested?. Knowing whether you have sperm DNA damage can help you make informed decisions about the type of treatment and/or lifestyle changes to improve your sperm DNA and fertility.. Can I improve my sperm DNA?. DNA damage is usually caused by oxidative stress. Oxidative stress produces free radicals which attack the DNA molecule causing breaks in the DNA strands. Sperm DNA damage is often associated with underlying medical conditions (such as varicocoele, infection or fever) or certain lifestyle choices (such as smoking or heat).. Your ...
TY - JOUR. T1 - Undamaged DNA transmits and enhances DNA damage checkpoint signals in early embryos. AU - Peng, Aimin. AU - Lewellyn, Andrea L.. AU - Maller, James L.. PY - 2007/10/1. Y1 - 2007/10/1. N2 - In Xenopus laevis embryos, the midblastula transition (MBT) at the 12th cell division marks initiation of critical developmental events, including zygotic transcription and the abrupt inclusion of gap phases into the cell cycle. Interestingly, although an ionizing radiation-induced checkpoint response is absent in pre-MBT embryos, introduction of a threshold amount of undamaged plasmid or sperm DNA allows a DNA damage checkpoint response to be activated. We show here that undamaged threshold DNA directly participates in checkpoint signaling, as judged by several dynamic changes, including H2AX phosphorylation, ATM phosphorylation and loading onto chromatin, and Chk1, Chk2 phosphorylation and release from nuclear DNA. These responses on physically separate threshold DNA require γ-H2AX and are ...
Background Dot1L, a histone methyltransferase that targets histone H3 lysine 79 (H3K79), has been implicated in gene regulation and the DNA damage response although its functions in these processes remain poorly defined. Methodology/Principal Findings Using the chicken DT40 model system, we generated cells in which the Dot1L gene is disrupted to examine the function and focal recruitment of the 53Bp1 DNA damage response protein. Detailed kinetic and dose response assays demonstrate that, despite the absence of H3K79 methylation demonstrated by mass spectrometry, 53Bp1 focal recruitment is not compromised in these cells. We also describe, for the first time, the phenotypes of a cell line lacking both Dot1L and 53Bp1. Dot1L¿/¿ and wild type cells are equally resistant to ionising radiation, whereas 53Bp1¿/¿/Dot1L¿/¿ cells display a striking DNA damage resistance phenotype. Dot1L and 53Bp1 also affect the expression of many genes. Loss of Dot1L activity dramatically alters the mRNA levels of ...
The DNA damage response (DDR) is a signal transduction pathway that decides the cells fate either to repair DNA damage or to undergo apoptosis if there is too much damage. Post-translational modifications modulate the assembly and activity of protein complexes during the DDR pathways. MicroRNAs (miRNAs) are emerging as a class of endogenous gene modulators that control protein levels, thereby adding a new layer of regulation to the DDR. In this review, we describe a new role for miRNAs in regulating the cellular response to DNA damage with a focus on DNA double-strand break damage. We also discuss the implications of miRNAs role in the DDR to stem cells, including embryonic stem cells and cancer stem cells, stressing the potential applications for miRNAs to be used as sensitizers for cancer radiotherapy and chemotherapy.
The excision of mutagenic DNA adducts by the nucleotide excision repair (NER) pathway is essential for genome stability, which is key to avoiding genetic diseases, premature aging, cancer and neurologic disorders. Due to the need to process an extraordinarily high damage density embedded in the nucleosome landscape of chromatin, NER activity provides a unique functional caliper to understand how histone modifiers modulate DNA damage responses. At least three distinct lysine methyltransferases (KMTs) targeting histones have been shown to facilitate the detection of ultraviolet (UV) light-induced DNA lesions in the difficult to access DNA wrapped around histones in nucleosomes. By methylating core histones, these KMTs generate docking sites for DNA damage recognition factors before the chromatin structure is ultimately relaxed and the offending lesions are effectively excised. In view of their function in priming nucleosomes for DNA repair, mutations of genes coding for these KMTs are expected to cause
The circadian control of an organisms response to DNA damage response rests upon circadian proteins which play important roles in the processes of cell proliferation and control of response to genotoxic stress both at the cellular and organismal levels [83]. DNA damage triggers cellular stress response pathways which may result in checkpoint cell cycle arrest, apoptosis or DNA repair. DNA damage leads to activation of critical components of cellular stress response pathways including ATM/ATR (ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related) and CHK1/2 (checkpoint kinase1/2) which in turn activates tumour suppressor protein p53 and subsequently causes cell cycle arrest or apoptosis [84]. It has been shown that Bmal1-deficient human cells are unable to undergo growth arrest on p53 activation by DNA damage. Contrary to in vivo mouse data connecting BMAL1-dependent delay in G1 progression to upregulation of p21 [82], radiation induced growth arrest in Bmal1-deficient human ...
One function of cell cycle checkpoints is to integrate cell cycle progression with DNA replication and repair. Therefore, the integrity of these checkpoints is considered essential in maintaining genetic stability. Mutations in checkpoint components may lead to aberrant cell cycle progression and, in the presence of DNA damage, may lead to subsequent genetic instability. DNA damage triggers a variety of cellular responses, including activation of DNA damage response pathways. In fission yeast, genetic evidence pointed to a model in which five checkpoint Rad proteins, Rad1, Rad9, Rad17, Rad26, and Hus1, sense DNA alterations and then cooperate to send a signal through Rad3 (1) . Rad3 can also function in the absence of several of these Rad genes, suggesting that Rad3 may interact with other proteins involved in the DNA damage response (4) .. In S. pombe the cell cycle checkpoint gene Rad1 is required to ensure that mitosis does not occur in the presence of DNA damage (8 , 9) . X-Spy1 was ...
Strand breaks in cellular DNA occur continuously as a consequence of normal processes such as recombination or the infliction of DNA damage. DNA damage triggers several signal transduction pathways that lead either to damage repair coupled with attenuation of cell cycle progression, or to programmed cell death (apoptosis). A junction of such pathways is controlled by the transcription factor p53. After DNA damage, the amount of p53 in cells is increased through posttranscriptional mechanisms and its transactivation activity is enhanced, leading to the activation of downstream genes (1).. The genetic disorder A-T results in genome instability, cerebellar and thymic degeneration, immunodeficiency, gonadal dysgenesis, radiation sensitivity, and predisposition to cancer. A-T cells exhibit acute sensitivity to ionizing radiation and radiomimetic chemicals, and their cell cycle checkpoints fail to be activated after treatment with these agents (2). The responsible gene, ATM, encodes a 370-kD protein ...
PubMedID: 23220418 | Dimer exchange and cleavage specificity of the DNA damage response protein UmuD. | Biochimica et biophysica acta | 2/1/2013
This is the first out of two pathways which deals with the DNA damage response. It is comprised of two central gene products (ATM and ATR) influenced by different sources of DNA damage (in blue). The two central genes can both be divides into their most important genes. For the ATM pathway these are TP53 and CHEK2, while CHEK1 is most important for the ATR pathway. The goal of this first pathway is to provide an overview of the most important gene products, processes and changes in cell condition elicited by the DNA damage response while keeping it clear and understandable. Also some microRNAs are implemented to visualize the possible effects they can induce. By doing so a better understanding of the role microRNA play in the DNA damage response might arise. All processes take place in the cytoplasm, except when mentioned differently. ...
DNA replication forks that are stalled by DNA damage activate an S-phase checkpoint that prevents irreversible fork arrest and cell death. The increased cell death caused by DNA damage in budding yeast cells lacking the Rad53 checkpoint protein kinase is partially suppressed by deletion of the gene. Using a whole-genome sequencing approach, we identified two additional genes, and , whose mutation can also partially suppress this DNA damage sensitivity. We provide evidence that and act in a common pathway, which is distinct from the pathway. Analysis of additional mutants indicates that suppression works through the loss of the Rpd3L histone deacetylase complex. Our results suggest that the loss or absence of histone acetylation, perhaps at stalled forks, may contribute to cell death in the absence of a functional checkpoint. ...
TY - JOUR. T1 - Maintenance of the DNA-damage checkpoint requires DNA-damage-induced mediator protein oligomerization. AU - Usui, Takehiko AU - Foster, Steven. AU - Petrini, John H. J.. N1 - Open Archive. PY - 2009/1/30. Y1 - 2009/1/30. N2 - Oligomeric assembly of Brca1 C-terminal (BRCT) domain-containing mediator proteins occurs at sites of DNA damage. However, the functional significance and regulation of such assemblies are not well understood. In this study, we defined the molecular mechanism of DNA-damage-induced oligomerization of the S. cerevisiae BRCT protein Rad9. Our data suggest that Rad9s tandem BRCT domain mediates Rad9 oligomerization via its interaction with its own Mec1/Tel1-phosphorylated SQ/TQ cluster domain (SCD). Rad53 activation is unaffected by mutations that impair Rad9 oligomerization, but checkpoint maintenance is lost, indicating that oligomerization is required to sustain checkpoint signaling. Once activated, Rad53 phosphorylates the Rad9 BRCT domain, which attenuates ...
CRISPR/Cas9 induces DNA double-strand breaks that are repaired by cell-autonomous repair pathways, namely, non-homologous end-joining (NHEJ), or homology-directed repair (HDR). While HDR is absent in G1, NHEJ is active throughout the cell cycle and, thus, is largely favored over HDR. We devised a strategy to increase HDR by directly synchronizing the expression of Cas9 with cell-cycle progression. Fusion of Cas9 to the N-terminal region of human Geminin converted this gene-editing protein into a substrate for the E3 ubiquitin ligase complex APC/Cdh1, resulting in a cell-cycle-tailored expression with low levels in G1 but high expression in S/G2/M. Importantly, Cas9-hGem(1/110) increased the rate of HDR by up to 87% compared to wild-type Cas9. Future developments may enable high-resolution expression of genome engineering proteins, which might increase HDR rates further, and may contribute to a better understanding of DNA repair pathways due to spatiotemporal control of DNA damage induction ...
The kinase ATM is classically known for its role in coordinating the response to DNA damage. DNA damage is caused by various intracellular and extracellular stimuli, including oxidative stress and free radicals. Lee et al. found critical amino acid residues that enable ATM to coordinate a response to DNA damage that is independent of its response to oxidative stress. Activation of ATM by either pathway promoted mitochondrial function and autophagy, thus mediating cell survival through metabolic changes. ATM activation via oxidative stress additionally promoted the clearance of toxic protein aggregates. These findings expand the roles of ATM and suggest that the loss of ATM function, such as in the neurodegenerative disease ataxia telangiectasia (A-T), causes broader cellular stress than that limited to a defective DNA damage response. ...
DNA damage (or RNA damage in the case of some virus genomes) appears to be a fundamental problem for life. As noted by Haynes,[14] the subunits of DNA are not endowed with any peculiar kind of quantum mechanical stability, and thus DNA is vulnerable to all the chemical horrors that might befall any such molecule in a warm aqueous medium. These chemical horrors are DNA damages that include various types of modification of the DNA bases, single- and double-strand breaks, and inter-strand cross-links (see DNA damage (naturally occurring). DNA damages are distinct from mutations although both are errors in the DNA. Whereas DNA damages are abnormal chemical and structural alterations, mutations ordinarily involve the normal four bases in new arrangements. Mutations can be replicated, and thus inherited when the DNA replicates. In contrast, DNA damages are altered structures that cannot, themselves, be replicated. Several different repair processes can remove DNA damages (see chart in DNA repair). ...
Time resolved data of DNA damage and repair after radiotherapy elucidates the relation between damage, repair, and cell survival. While well characterized in vitro, little is known about the time-course of DNA damage response in tumors sampled from individual patients. Kinetics of DNA damage after radiotherapy was assessed in eight dogs using repeated in vivo samples of tumor and co-irradiated normal tissue analyzed with comet assay and phosphorylated H2AX (γH2AX) immunohistochemistry. In vivo results were then compared (in silico) with a dynamic mathematical model for DNA damage formation and repair. Maximum %DNA in tail was observed at 15-60 min after irradiation, with a rapid decrease. Time-courses of γH2AX-foci paralleled these findings with a small time delay and were not influenced by covariates. The evolutionary parameter search based on %DNA in tail revealed a good fit of the DNA repair model to in vivo data for pooled sarcoma time-courses, but fits for individual sarcoma time-courses suffer
By Kristian Moss Bendtsen, Jeppe Juul, Ala Trusina. DNA damages, as well as mutations, increase with age. It is believed that these result from increased genotoxic stress and decreased capacity for DNA repair. The two causes are not independent, DNA damage can, for example, through mutations, compromise the capacity for DNA repair, which in turn increases the amount of unrepaired DNA damage. Despite this vicious circle, we ask, can cells maintain a high DNA repair capacity for some time or is repair capacity bound to continuously decline with age? We here present a simple mathematical model for ageing in multicellular systems where cells subjected to DNA damage can undergo full repair, go apoptotic, or accumulate mutations thus reducing DNA repair capacity. Our model predicts that at the tissue level repair rate does not continuously decline with age, but instead has a characteristic extended period of high and non-declining DNA repair capacity, followed by a rapid decline. Furthermore, the time ...
Upon viral infection, the major defense mounted by the host innate immune system is activation of the IFN- and apoptosis-mediated antiviral pathway. In order to complete their life cycle, viruses that are obligatory intracellular parasites must modulate these host immune responses. We have previously shown that the γHV68 latency-associated M2 protein effectively downregulates STAT1 and STAT2, resulting in the inhibition of type I and II IFN-mediated transcriptional activation. Here, we demonstrate that M2 interacts with ATM, a DNA damage signal transducer, and the DDB1/COP9/cullin DNA damage effector complex. This interaction blocked DNA damage-sensing activity as well as DNA damage repair activity, thereby rendering cells resistant to DNA damage-induced apoptosis. These results indicate that γHV68 encodes M2, a latency-associated gene, to antagonize both IFN- and apoptosis-mediated host innate immunities and thus is important in establishing and maintaining viral latency in infected ...
The endoribonuclease Dicer is a key component of the human RNA interference pathway and is known for its role in cytoplasmic microRNA production. Recent findings suggest that noncanonical Dicer generates small noncoding RNA to mediate the DNA damage response (DDR). Here, we show that human Dicer is phosphorylated in the platform-Piwi/Argonaute/Zwille-connector helix cassette (S1016) upon induction of DNA damage. Phosphorylated Dicer (p-Dicer) accumulates in the nucleus and is recruited to DNA double-strand breaks. We further demonstrate that turnover of damage-induced nuclear, double-stranded (ds) RNA requires additional phosphorylation of carboxy-terminal Dicer residues (S1728 and S1852). DNA damage-induced nuclear Dicer accumulation is conserved in mammals. Dicer depletion causes endogenous DNA damage and delays the DDR by impaired recruitment of repair factors MDC1 and 53BP1. Collectively, we place Dicer within the context of the DDR by demonstrating a DNA damage-inducible phosphoswitch that causes
This is the first pathway out of two pathways which deals with DNA damage response. It has two central gene products (ATM and ATR) which are connected to the sources of DNA damage (in blue). The two central genes can be divides furthermore into their most important genes. In the ATM pathway are the most important genes TP53 and CHEK2 and on the other hand in the ATR pathway is this CHEK1. If it is not mentioned different, the processes take place in the cell cytoplasm. The goal of this first pathway is to give an overview of the most important gene products, processes and changes in the cell condition through the DNA damage response pathway and at the same time to keep it clearly ...
MCC is a potential tumor suppressor gene, which is silenced by promoter hypermethylation in a subset of colorectal cancers. However, its functions have remained poorly understood. In the present study, we describe a novel function of MCC in the DNA damage response. Several novel phosphorylation sites were identified by mass spectrometry, including 2 highly conserved ATM/ATR consensus sites at serine 118 and serine 120. In addition, exposure to ultraviolet radiation (UV), but not phleomycin, caused PI3K-dependent phosphorylation of MCC and its nuclear localization. Re-expression of MCC in HCT15 colorectal cancer cells led to a G2/M arrest, and MCC knockdown impaired the induction of a G2/M arrest following UV radiation. Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. Thus, these results suggest that MCC is a novel target of the DNA damage checkpoint and that MCC is required for the complete cell cycle arrest in the G2
The 25 gene deletions that conferred increased Dna2 foci were strongly enriched for genes involved in DNA repair and DNA damage response (Figure 4B) (P = 2×10−17 and P = 5×10−16). We compared these genes to those identified in a recent constitutive RNR3 expression screen (Hendry et al. 2015) and found significant overlap (16 genes, hypergeometric P = 4×10−21), suggesting the presence of increased spontaneous DNA damage in these mutants, as expression of RNR3 responds specifically to DNA damage (Elledge and Davis 1990). We compared the genes that, when deleted, caused increased Dna2 foci to those that cause increased Rad52 foci (Alvaro et al. 2007), again finding significant overlap (10 genes, hypergeometric P = 2×10−11). Finally, we compared the set of genes with negative genetic interactions with dna2-1 or dna2-2 (Budd et al. 2005), which could indicate spontaneous damage that requires Dna2 for its repair. We noted a significant overlap (10 genes, hypergeometric P = 2×10−14). ...
Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging. We generated flies with knockdown of Mre11, Rad50, Nbs1, ATM, ATR, Chk1, and Chk2, which decrease the DDR system in ECs. EC-specific DDR depletion induced EC death, accelerated the aging of ISCs, as evidenced by ISC hyperproliferation, DNA damage accumulation, and increased centrosome amplification, and affected the adult flys survival. Our data
Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging. We generated flies with knockdown of Mre11, Rad50, Nbs1, ATM, ATR, Chk1, and Chk2, which decrease the DDR system in ECs. EC-specific DDR depletion induced EC death, accelerated the aging of ISCs, as evidenced by ISC hyperproliferation, DNA damage accumulation, and increased centrosome amplification, and affected the adult flys survival. Our data
In mammalian cells, RB/E2F and p53 are intimately connected, and crosstalk between these pathways is critical for the induction of cell cycle arrest or cell death in response to cellular stresses. Here we have investigated the genetic interactions between RBF/E2F and p53 pathways during Drosophila development. Unexpectedly, we find that the pro-apoptotic activities of E2F and p53 are independent of one another when examined in the context of Drosophila development: apoptosis induced by the deregulation of dE2F1, or by the overexpression of dE2F1, is unaffected by the elimination of dp53; conversely, dp53-induced phenotypes are unaffected by the elimination of dE2F activity. However, dE2F and dp53 converge in the context of a DNA damage response. Both dE2F1/dDP and dp53 are required for DNA damage-induced cell death, and the analysis of rbf1 mutant eye discs indicates that dE2F1/dDP and dp53 cooperatively promote cell death in irradiated discs. In this context, the further deregulation in the expression
Radiotherapy resistance is one of the major factors limiting the efficacy of radiotherapy in lung cancer patients. The extensive investigations indicate the diversity in the mechanisms underlying radioresistance. Here, we revealed that DNA damage binding protein 2 (DDB2) is a potential regulator in the radiosensitivity of non-small cell lung cancer (NSCLC) cells. DDB2, originally identified as a DNA damage recognition factor in the nucleotide excision repair, promotes the survival and inhibits the apoptosis of NSCLC cell lines upon ionizing radiation (IR). Mechanistic investigations demonstrated that DDB2 is able to facilitate IR-induced phosphorylation of Chk1, which plays a critical role in the cell cycle arrest and DNA repair in response to IR-induced DNA double-strand breaks (DSBs). Indeed, knockdown of DDB2 compromised the G2 arrest in the p53-proficient A549 cell line and reduced the efficiency of homologous recombination (HR) repair. Taken together, our data indicate that the expression of DDB2
Stress overload of the DDR pathway should also show efficacy in cancer treatment. Although it is not clear why DNA damaging agents, such as IR and chemotherapy, are effective cancer therapies, it is possible that these are examples of stress overload, where cancer cells with already elevated levels of DNA damage and replication stress cannot repair the additional damage inflicted by these agents. An alternative explanation is that during tumorigenesis, the persistence of DNA damage selects for cells with mutations that abrogate part of the DDR pathway and therefore cannot properly sense and respond to DNA damage. These cells with a partially defective DDR might therefore be more vulnerable to the extensive DNA damage resulting from radiation or chemotherapy that is lethal without a normal DDR pathway. In this context, DNA damage exploits a stress phenotype of tumors that is analogous to non-oncogene addition.. Given the sensitivity of many cancers to DNA damaging agents, there should exist genes ...
Research has indicated that oxidative stress is the cause of many serious diseases such as cancer, Alzheimers, arteriosclerosis and diabetes.
DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cy …
Emerging data strongly suggest that the oxidation of DNA bases can contribute to genomic instability. Structural changes to DNA, induced by base oxidation, may reduce the fidelity of DNA replication and interfere with sequence-specific DNA−protein interactions. We have examined the structures of a series of pyrimidine deoxynucleoside oxidation damage products in aqueous solution. The modified nucleosides studied include the deoxynucleoside derivatives of 5-hydroxyuracil, 5-hydroxycytosine, 5-(hydroxymethyl)uracil, 5-(hydroxymethyl)cytosine, 5-formyluracil, and 5-formylcytosine. The influence of base oxidation on ionization constants, sugar conformation, and tautomeric configuration has been determined on the basis of UV, proton, and nitrogen NMR spectra of the ^(15)N-enriched derivatives. The potential biological consequences of the structural perturbations resulting from base oxidation are discussed. ...
DNA damage and repair and their role in carcinogenesis A DNA sequence can be changed by copying errors introduced by DNA polymerase during replication and by environmental agents such as chemical mutagens or radiation If uncorrected, such changes may interfere with the ability of the cell to function DNA damage can be repaired by several mechanisms All carcinogens cause changes in the DNA sequence and thus DNA damage and repair are important aspects in the development of cancer Prokaryotic and eukaryotic DNA-repair systems are analogous
Cells of metazoan organisms respond to DNA damage by arresting their cell cycle to repair DNA, or they undergo apoptosis. Two protein kinases, ataxia-telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR), are sensors for DNA damage. In humans, ATM is mutated in patients with ataxia-telangiectasia (A-T), resulting in hypersensitivity to ionizing radiation (IR) and increased cancer susceptibility. Cells from A-T patients exhibit chromosome aberrations and excessive spontaneous apoptosis. We used Drosophila as a model system to study ATM function. Previous studies suggest that mei-41 corresponds to ATM in Drosophila; however, it appears that mei-41 is probably the ATR ortholog. Unlike mei-41 mutants, flies deficient for the true ATM ortholog, dATM, die as pupae or eclose with eye and wing abnormalities. Developing larval discs exhibit substantially increased spontaneous chromosomal telomere fusions and p53-dependent apoptosis. These developmental phenotypes are unique to dATM, and both dATM ...
TY - JOUR. T1 - The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph - acute lymphoblastic leukemia cells. AU - Scuto, Anna. AU - Kirschbaum, Mark. AU - Kowolik, Claudia. AU - Kretzner, Leo. AU - Juhasz, Agnes. AU - Atadja, Peter. AU - Pullarkat, Vinod. AU - Bhatia, Ravi. AU - Forman, Stephen. AU - Yen, Yun. AU - Jove, Richard. PY - 2008/5/15. Y1 - 2008/5/15. N2 - We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome-negative (Ph -) acute lymphoblastic leukemia (ALL). Two model human Ph - ALL cell lines (T-cell MOLT-4 and pre-B-cell Reh) were treated with LBH589 and evaluated for biologic and gene expression responses. Low nanomolar concentrations (IC 50:5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA ...
TY - JOUR. T1 - Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint. AU - Shimura, T.. AU - Toyoshima, M.. AU - Adiga, S. K.. AU - Kunoh, T.. AU - Nagai, H.. AU - Shimizu, N.. AU - Inoue, M.. AU - Niwa, O.. PY - 2006/9/28. Y1 - 2006/9/28. N2 - The S-phase DNA damage checkpoint is activated by DNA damage to delay DNA synthesis allowing time to resolve the replication block. We previously discovered the p53-dependent S-phase DNA damage checkpoint in mouse zygotes fertilized with irradiated sperm. Here, we report that the same p53 dependency holds in mouse embryonic fibroblasts (MEFs) at low doses of irradiation. DNA synthesis in p53 wild-type (WT) MEFs was suppressed in a biphasic manner in which a sharp decrease below 2.5 Gy was followed by a more moderate decrease up to 10 Gy. In contrast, p53-/- MEFs exhibited radioresistant DNA synthesis below 2.5 Gy whereas the cells retained the moderate suppression above 5 Gy. DNA fiber analysis ...
TY - JOUR. T1 - DNA damage and breast cancer risk. AU - Smith, Tasha R.. AU - Miller, Mark S.. AU - Lohman, Kurt K.. AU - Case, L. Douglas. AU - Hu, Jennifer H.. PY - 2003/5/1. Y1 - 2003/5/1. N2 - To evaluate whether deficient DNA repair contributes to elevated DNA damage and breast carcinogenesis, we used the comet assay (single-cell alkaline gel electrophoresis) to measure the levels of DNA damage in peripheral lymphocytes from 70 breast cancer cases and 70 controls. DNA damage, measured as the comet tail moment, was not influenced by age, family history (FH), age at menarche, age at first birth or parity. The results showed that cancer cases had significantly higher DNA damage compared with controls; the comet tail moments (mean ± SD) for cases and controls were: 10.78 ± 3.63 and 6.86 ± 2.76 (P , 0.001) for DNA damage at baseline (DB), 21.24 ± 4.88 and 14.97 ± 4.18 (P , 0.001) for DNA damage after exposure to 6 Gy of ionizing radiation (DIR), and 14.76 ± 5.35 and 9.75 ± 3.35 (P , ...
Compounds of nickel(II) and cadmium(II) are carcinogenic to humans and to experimental animals. One frequently discussed mechanism involved in tumor formation is an increase in reactive oxygen species by both metals with the subsequent generation of oxidative DNA damage. In the present study we used human HeLa cells to investigate the potential of nickel(II) and cadmium(II) to induce DNA lesions typical for oxygen free radicals in intact cells and the effect on their repair. As indicators of oxidative DNA damage, we determined the frequencies of DNA strand breaks and of lesions recognized by the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein), including 7,8-dihydro-8-oxoguanine (8-hydroxyguanine), a pre-mutagenic DNA base modification. Nickel(II) caused a slight increase in DNA strand breaks at 250 microM and higher, while the frequency of Fpg-sensitive sites was enhanced only at the cytotoxic concentration of 750 microM. The repair of oxidative DNA lesions induced by visible light ...
To investigate how the nucleotide excision repair initiator XPC locates DNA damage in mammalian cell nuclei we analyzed the dynamics of GFP-tagged XPC. Photobleaching experiments showed that XPC constantly associates with and dissociates from chromatin in the absence of DNA damage. DNA-damaging agents retard the mobility of XPC, and UV damage has the most pronounced effect on the mobility of XPC-GFP. XPC exhibited a surprising distinct dynamic behavior and subnuclear distribution compared with other NER factors. Moreover, we uncovered a novel regulatory mechanism for XPC. Under unchallenged conditions, XPC is continuously exported from and imported into the nucleus, which is impeded when NER lesions are present. XPC is omnipresent in the nucleus, allowing a quick response to genotoxic stress. To avoid excessive DNA probing by the low specificity of the protein, the steady-state level in the nucleus is controlled by nucleus-cytoplasm shuttling, allowing temporally higher concentrations of XPC in ...
Cancer is one of the most unwanted menaces in the human body. Cancers of lower abdomen are not only life threatening but also painful and survival rate is low. Cervical cancer is second most common worldwide and fifth deadliest in women. It affects about 16 per 100,000 women per year and kills about 9 per 100,000 in a year. In developing countries occurrence rate is 80%. It is possible that there may be no symptom until an advance stage of the cancer is progressed. The single cell gel electrophoresis assay also called comet assay, which is versatile, reliable, powerful, uncomplicated and sensitive technique for detection of DNA damage at the level of individual eukaryotic cell. Understanding the extent of DNA damage in neoplastic cells discarded in the urine of cancer patients through comet assay. Usually normal urine sample have very rare cells. In case of cancer patient the number of cells increases drastically. The type of cells passed in the urine of cancer patient contains mainly ...
Many cancers display both structural (s-CIN) and numerical (w-CIN) chromosomal instabilities. Defective chromosome segregation during mitosis has been shown to cause DNA damage that induces structural rearrangements of chromosomes (s-CIN). In contrast, whether DNA damage can disrupt mitotic processes to generate whole chromosomal instability (w-CIN) is unknown. Here we show that activation of the DNA damage response (DDR) during mitosis selectively stabilizes kinetochore-microtubule (k-MT) attachments to chromosomes through Aurora-A and Plk1 kinases, thereby increasing the frequency of lagging chromosomes during anaphase. Inhibition of DDR proteins, ATM or Chk2, abolishes the effect of DNA damage on k-MTs and chromosome segregation, whereas activation of the DDR in the absence of DNA damage is sufficient to induce chromosome segregation errors. Finally, inhibiting the DDR during mitosis in cancer cells with persistent DNA damage suppresses inherent chromosome segregation defects. Thus, DDR ...
Coordination of the multiple processes underlying DNA replication is key for maintaining genome stability and preventing tumorigenesis. CLASPIN, a critical player in replication fork stabilization and checkpoint responses, must be tightly regulated during the cell cycle to prevent the accumulation of DNA damage. In this study, we used a quantitative proteomics approach and identified USP9X as a novel CLASPIN-interacting protein. USP9X is a deubiquitinase involved in multiple signaling and survival pathways whose tumor suppressor or oncogenic activity is highly context dependent. We found that USP9X regulated the expression and stability of CLASPIN in an S-phase-specific manner. USP9X depletion profoundly impairs the progression of DNA replication forks, causing unscheduled termination events with a frequency similar to CLASPIN depletion, resulting in excessive endogenous DNA damage. Importantly, restoration of CLASPIN expression in USP9X-depleted cells partially suppressed the accumulation of ...
TY - JOUR. T1 - Comparison of UVB and UVC effects on the DNA damage-response protein 53BP1 in human pancreatic cancer. AU - Uehara, Fuminari. AU - Miwa, Shinji. AU - Tome, Yasunori. AU - Hiroshima, Yukihiko. AU - Yano, Shuya. AU - Yamamoto, Mako. AU - Efimova, Elena. AU - Matsumoto, Yasunori. AU - Maehara, Hiroki. AU - Bouvet, Michael. AU - Kanaya, Fuminori. AU - Hoffman, Robert M.. N1 - Copyright: Copyright 2016 Elsevier B.V., All rights reserved.. PY - 2014/10. Y1 - 2014/10. N2 - We have previously demonstrated that ultraviolet (UV) light is effective against a variety of cancer cells expressing fluorescent proteins in vivo as well as in vitro. In the present report, we compared the DNA damage repair (DDR) response of pancreatic cancer cells after UVB or UVC irradiation. The UV-induced DNA damage repair was imaged with green fluorescent protein (GFP) fused to the DDR-related chromatin-binding protein 53BP1 in MiaPaCa-2 human pancreatic cancer cells growing in 3D Gelfoam® histoculture and in ...
TY - JOUR. T1 - Yeast Rap1 contributes to genomic integrity by activating DNA damage repair genes. AU - Tomar, Raghuvir S.. AU - Zheng, Suting. AU - Brunke-Reese, Deborah. AU - Wolcott, Holly N.. AU - Reese, Joseph C.. N1 - Copyright: Copyright 2008 Elsevier B.V., All rights reserved.. PY - 2008/6/4. Y1 - 2008/6/4. N2 - Rap1 (repressor-activator protein 1) is a multifunctional protein that controls telomere function, silencing and the activation of glycolytic and ribosomal protein genes. We have identified a novel function for Rap1, regulating the ribonucleotide reductase (RNR) genes that are required for DNA repair and telomere expansion. Both the C terminus and DNA-binding domain of Rap1 are required for the activation of the RNR genes, and the phenotypes of different Rap1 mutants suggest that it utilizes both regions to carry out distinct steps in the activation process. Recruitment of Rap1 to the RNR3 gene is dependent on activation of the DNA damage checkpoint and chromatin remodelling by ...
Here, we report that genome editing by CRISPR-Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR-Cas9. CRISPR-Cas9-induced DNA damage triggers p53 to limit the efficiency of gene editing in immortalized human retinal pigment epithelial cells.
The Comet Assay, also called single cell gel electrophoresis (SCGE), is a sensitive and rapid technique for quantifying and analyzing DNA damage in individual cells.
BACKGROUND. Chronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent protein kinase complex.. OBJECTIVES. To investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells.. METHODS. Protein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays.. RESULTS. 8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p = 0.0012) and patients with COPD ...
The recent observations that both DNA adducts and oxidative base damage are increased in the brains from Alzheimer s and Parkinson s patients and in spinal cord tissue of patients with amyotrophic lateral sclerosis (ALS) support the idea that oxidative DNA damage may contribute to the observed loss of neurons in these neurological disorders (8,9). Therefore, understanding how oxidative DNA damage is repaired (or not) is critical for understanding the pathology underlying these diseases. The overall hypothesis of this proposal is that oxidative stress induced DNA damage in neuronal cell lines leading to cellular malfunction and/or death and DNA repair enzymes are critical for the protection of neurons against oxidative stress. The following specific Aims will address this hypothesis. Specific Aim 1: Functional and biochemical characterization of the repair enzymes Ogg1, NTH, MTH, and MYH in the neuroblastoma cell lines SHSY5Y and Neuro-2A and in primary cultures of hippocampal neurons. We will ...
UV-induced damage can induce apoptosis or trigger DNA repair mechanisms. Minor DNA damage is thought to halt the cell cycle to allow effective repair, while more severe damage can induce an apoptotic program. Of the two major types of UV-induced DNA lesions, it has been reported that repair of CPD, but not 6-4PP, abrogates mutation. To address whether the two major forms of UV-induced DNA damage, can induce differential biological effects, NER-deficient cells containing either CPD photolyase or 6-4 PP photolyase were exposed to UV and examined for alterations in cell cycle and apoptosis. In addition, pTpT, a molecular mimic of CPD was tested in vitro and in vivo for the ability to induce cell death and cell cycle alterations. NER-deficient XPA cells were stably transfected with CPD-photolyase or 6-4PP photolyase to specifically repair only CPD or only 6-4PP. After 300 J/m2 UVB exposure photoreactivation light (PR, UVA 60 kJ/m2) was provided for photolyase activation and DNA repair. Apoptosis was
BioTek Note applicative, 07-Jul-16, Automated Comet Assay Imaging and Dual-Mask Analysis to Determine DNA Damage on an Individual Comet Basis
The underlying cause of cancer is spontaneous mutations introduced to genomic DNA. Reactive products of cellular metabolism and external genotoxic agents cause persistent DNA damage, which is constantly removed through various DNA repair mechanisms. It is unavoidable, however, that some DNA modifications (lesions) persist into S-phase, creating blocks for progression of the DNA replication machinery. To circumvent this problem organisms in all kingdoms of life have evolved DNA damage tolerance pathways, employing specialized enzymes that bypass DNA lesions while temporarily leaving DNA damage unrepaired. The vast majority of mutations are introduced in the genome by enzymes of error-prone branch of DNA damage tolerance - translesion DNA synthesis (TLS). Genetic changes that ensue as a result of TLS are at the root of the onset of cancer and the development of various resistance mechanisms displayed by relapsed tumors, which represents a major problem for treatment of some types of cancer, ...
Here, we demonstrate that OTUD4 may serve as a master regulator of alkylation damage resistance through stabilization of the human AlkB homologues. A number of distinct lines of evidence support this role for OTUD4. First, OTUD4 interacts specifically with ALKBH2 and ALKBH3 and encodes a K48‐specific DUB (Fig 1). Consistently, ALKBH3 is subjected to K48‐linked ubiquitination and proteasomal degradation (Fig 2A-D). OTUD4 antagonizes ALKBH3 ubiquitination and stabilizes both ALKBH2 and ALKBH3 in vivo (Fig 2E-H). ALKBH3 protein levels do not correlate well with ALKBH3 mRNA levels in various tumor cell lines but do correlate with OTUD4 levels (Supplementary Fig S2). Finally, overexpression of ALKBH3 in PC‐3 cells, which depend primarily on ALKBH3 instead of ALKBH2 for alkylation damage resistance, is sufficient to rescue alkylation damage sensitivity upon loss of OTUD4 (Fig 7G).. What is most striking is that we find OTUD4 catalytic activity to be apparently dispensable for its stabilization ...
The Mre11-Rad50-Nbs1 (MRN) complex has many biological functions: processing of double-strand breaks in meiosis, homologous recombination, telomere maintenance, S-phase checkpoint, and genome stability during replication. In the S-phase DNA damage checkpoint, MRN acts both in activation of checkpoint signaling and downstream of the checkpoint kinases to slow DNA replication. Mechanistically, MRN, along with its cofactor Ctp1, is involved in 5 resection to create single-stranded DNA that is required for both signaling and homologous recombination. However, it is unclear whether resection is essential for all of the cellular functions of MRN. To dissect the various roles of MRN, we performed a structure-function analysis of nuclease dead alleles and potential separation-of-function alleles analogous to those found in the human disease ataxia telangiectasia-like disorder, which is caused by mutations in Mre11. We find that several alleles of rad32 (the fission yeast homologue of mre11), along with
Nitric oxide (NO) as well as its donors has been shown to generate mutation and DNA damage in in vitro assays. The objective of this study was to identify that DNA single-strand breaks (SSBs) could be elicited by NO, not only in vitro but also in vivo. The alkaline single-cell gel electrophoresis (SCGE) was performed to examine the DNA damage in g12 cells and the cells isolated from the organs of mice exposed to sodium nitroprusside (SNP). A modified method, in which neither collagenase nor trypsin was necessary, was used to prepare the single-cell suspension isolated from organs of mice. Results showed that the exposure of g12 cells to 0.13-0.5 mu mol/ml SNP with S9 for 1 h induced a concentration-dependent increase in DNA SSBs in g12 cells. The significant increase in DNA migration and comet frequency has appeared in the cells isolated from the spleen, thymus, and peritoneal macrophages of mice after injecting i.p. SNP in the dosage range of 0.67-6.0 mg/kg b.wt for 1 h. However, no obvious ...
Article Effects of proton beams from the folded tandem ion accelerator on DNA damage in mouse leukocytes using the comet assay. Single cell gel electrophoresis or the comet assay is a sensitive technique to quantify different types of DNA damage, e.g...
This unit describes immunocytochemical detection of phosphorylated histone H2AX for revealing the presence of DNA double-strand breaks. Double-strand breaks indicate DNA damage induced by ionizing radiation or by treatment with antitumor drugs such as DNA topoisomerase inhibitors. However, double-strand breaks can also be intrinsic, occurring in healthy, nontreated cells for a variety of reasons, and are generated in the course of DNA fragmentation in apoptotic cells. The unit presents strategies to distinguish radiation- or drug-induced breaks from those intrinsically formed in untreated cells or associated with apoptosis. The protocol describes the immunocytochemical detection of histone H2AX phosphorylated on Ser-139 combined with measurement of DNA content to identify cells that have DNA double-strand breaks and to concurrently assess their cell cycle phase. The detection is based on indirect immunofluorescence using a FITC-labeled secondary antibody, and DNA is counterstained with propidium ...
Time-lapse imaging can make complicated processes easier to grasp-think of a stitched-together sequence of photos that chronicles the construction of a building. Now, scientists from the Department of Energys Lawrence Berkeley National Laboratory (Berkeley Lab) are using a similar approach to study how cells repair DNA damage.
TY - JOUR. T1 - Cytogenetic analysis of human cells reveals specific patterns of DNA damage in replicative and oncogene-induced senescence. AU - Falcone, Germana. AU - Mazzola, Alessia. AU - Michelini, Flavia. AU - Bossi, Gianluca. AU - Censi, Federica. AU - Biferi, Maria G.. AU - Minghetti, Luisa. AU - Floridia, Giovanna. AU - Federico, Maurizio. AU - Musio, Antonio. AU - Crescenzi, Marco. PY - 2013. Y1 - 2013. N2 - Senescence is thought to be triggered by DNA damage, usually indirectly assessed as activation of the DNA damage response (DDR), but direct surveys of genetic damage are lacking. Here, we mitotically reactivate senescent human fibroblasts to evaluate their cytogenetic damage. We show that replicative senescence is generally characterized by telomeric fusions. However, both telomeric and extratelomeric aberrations are prevented by hTERT, indicating that even non-telomeric damage descends from the lack of telomerase. Compared with replicative senescent cells, oncogene-induced ...
TY - JOUR. T1 - Defense mechanism to oxidative DNA damage in glial cells. AU - Iida, Takashi. AU - Furuta, Akiko. AU - Nakabeppu, Yusaku. AU - Iwaki, Toru. PY - 2004/6/1. Y1 - 2004/6/1. N2 - Astrocytosis is a sequential morphological change of astrocytic reaction to tissue damage, and is associated with regulation of antioxidant defense mechanisms to reduce oxidative damage. The repair enzymes to oxidative DNA damage, oxidized purine-nucleoside triphosphatase (hMTH1) and a mitochondrial type of 8-oxoguanine DNA glycosylase (hOGG1-2a) in brain tumors and neurons of Alzheimers disease, were previously reported. In the present study, glial expression of these repair enzymes under such pathological conditions as cerebrovascular diseases and metastatic brain tumors, were investigated. Furthermore, an in-vitro experiment using a glioma cell-line under oxidative stress was performed to verify the immunohistochemical results of post-mortem materials. As a result, hOGG1-2a immunoreactivities in reactive ...
L to R) David Jeruzalmi, Danaya Pakotiprapha, and Martin Samuels. DNA damage is a fact of life for all living organisms. Some have estimated that each of our human cells absorbs thousands of damaging events each and every day. Left uncorrected, such damage can lead to permanent, disruptive, changes in the genome, and cause various diseases including cancer. Without an active method of patrolling the genome for damage, and repairing it when found, life on earth would not last very long. Thus, all organisms deploy a panoply of DNA repair pathways. One of these, the nucleotide excision repair (NER) pathway, is unique for its ability to repair a chemically diverse set of lesions that each alters the structure of DNA in profoundly different ways. Conserved throughout evolution, NER involves several major steps: genome scanning, damage recognition, incision, and repair synthesis. Mutations in this pathway give rise to many human diseases including xeroderma pigmentosum, Cockayne syndrome, and ...
Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy. The sources of genome instability have only recently begun to be elucidated. A high frequency of externally caused DNA damage can be one source of genome instability since DNA damages can cause inaccurate translesion synthesis past the damages or errors in repair, leading to mutation. Another source of genome instability may be epigenetic or mutational reductions in expression of DNA repair genes. Because endogenous (metabolically-caused) DNA damage is very frequent, ...
Pro-carcinogens, such as benzoapyrene (BaP), that are exogenous ligands of the aromatic hydrocarbon receptor may influence the susceptibility of target-cell populations through the up-regulation of cytochrome P450 (CYP) mixed function oxidases. We examined whether the growth kinetics of MCF-7 cells might determine the level of up-regulation of CYP1A1, CYP1A2 or CYP1B1 by BaP, and whether this could then influence subsequent levels of DNA damage. Cell cultures manipulated to be G0/G1-phase concentrated, S-phase concentrated or G2/M-phase concentrated were treated with BaP and the expression levels of CYP1A1, CYP1A2, CYP1B1, cyclin-dependent kinase inhibitor 1A CDKN1A (P21WAF1/CIP1), B-cell leukaemia/lymphoma-2 (BCL-2), and Bcl-2-associated X levels were determined. Levels of DNA damage were measured as DNA single-strand breaks (SSBs) by the alkaline single-cell gel electrophoresis (comet) assay or as DNA adducts by 32P-postlabelling analysis. BaP-induced up-regulation of CYP1A1 was ...
Every day we are exposed to carcinogens, including ultraviolet radiation (UVR). High levels of ultraviolet radiation are known to cause DNA damage. One of the most common forms of UVR-induced damage, the pyrimidine dimer, is repaired by an enzymatic reaction powered by visible light. We wanted to find out if there is variation in the level of UVR-induced DNA damage induced in two different clones of Daphnia magna, a model organism for ecotoxicology. One clone was derived from a mid-latitude deep reservoir, where escape from UVR is possible via vertical migration. The second clone was from a high-latitude shallow rock pool, where D. magna are exposed to high levels of UVR. Pregnant mothers from each clone line were subjected to ecologically relevant levels of UVR in the lab. Immediately afterwards, we extracted the embryos, suspended the cells in agarose, and performed a comet assay, which allows for quantification of DNA damage within individual cells. The slides were viewed under a fluorescent
Morphological transformation of C3H/M2 mouse fibroblasts by, and genotoxicity of, extracts of human milk. Breast cancer may be initiated by environmental/dietary agents and human milk may act as an ex vivo indicator of in vivo exposure of mammary epithelial cells to genotoxins. Extracts of human milk from UK-resident women (n = 7) were tested for their abilities to morphologically transform C3H/M2 mouse fibroblasts. Genotoxicities were assessed in the Salmonella typhimurium reverse-mutation assay in the presence of S9 using strains TA1538 and YG1019, and in metabolically-competent human MCL-5 cells with the micronucleus and with the alkaline single cell gel electrophoresis (comet) assays. Two of the seven extracts were inactive in the transformation assay both in the presence or absence of S9, two appeared to be equally transforming either in the presence or absence of S9, and two other extracts induced increased transformation frequencies in the presence of S9. A seventh extract, tested only in ...
Autophagy and the DNA damage response (DDR) are biological processes essential for cellular and organismal homeostasis. Herein we summarize and discuss emerging evidence linking DDR to autophagy. We highlight published data suggesting that autophagy is activated by DNA damage and is required for several functional outcomes of DDR signaling, including repair of DNA lesions, senescence, cell death, and cytokine secretion. Uncovering the mechanisms by which autophagy and DDR are intertwined provides novel insight into the pathobiology of conditions associated with accumulation of DNA damage, including cancer and aging, and novel concepts for the development of improved therapeutic strategies against these pathologies.
Among numerous types of oxidative DNA damage, 8-hydroxydeoxyguanosine (8-OHdG) is a ubiquitous marker of oxidative stress. 8-OHdG, one of the byproducts of oxidative DNA damage, is physiologically formed and enhanced by chemical carcinogens. Our OxiSelect™ Oxidative DNA Damage ELISA Kit (8-hydroxydeoxyguanosine assay) provides a powerful method for rapid, sensitive quantitation of 8-OHdG in DNA samples.
The promoter of nrdA gene which is related with DNA synthesis was used to construct a DNA damage sensitive biosensor. A recombinant bioluminescent E. coli strain, BBTNrdA, harboring a plasmid with the nrdA promoter fused to the luxCDABE operon, was successfully constructed. Its response to various chemicals including genotoxic chemicals substantiates it as a DNA damage biosensor. In characterization, three different classes of toxicants were used: DNA damaging chemicals, oxidative stress chemicals, and phenolics. BBTNrdA only responded strongly to DNA damaging chemicals, such as nalidixic acid (NDA), mitomycin C (MMC), 1-methyl-1-nitroso-N-methylguanidine (MNNG), and 4-nitroquinoline N-oxide (4-NQO). In contrast, there were no responses from the oxidative stress chemicals and phenolics, except from hydrogen peroxide (H2O2) which is known to cause DNA damage indirectly. Therefore, the results of the study demonstrate that BBTNrdA can be used as a DNA damage biosensor.
The Comet Assay for detection of DNA repair and DNA damage by tail intensity. In Comet Assays the damage is detected with the single-stranded or double-stranded DNA breaks. DNA damage can be induced by chemicals or UV light radiation. A single cell is paced in low melting agarose on a microscope slide. The cell membrane will be lysed with detergent and salt concentration. Nucleotides will be released from the nucleus and electrophoresis will migrate the damaged DNA to the + anode electric field. The more the DNA is damaged the more there will appear a migration tail. Endonucleases damage increases the DNA migration, whereas DNA-DNA and DNA-protein cross-links result in retarded DNA migration, Tice, 2000. The comet assay is used in DNA repair studies, in animal and clinical studies for base excision repair (BER), nucleotide excision repair (NER) like the Vitotox L. Gevaert, 2009 measures the cytotoxicity in Salmonella lux promotor cloned cells. They show that the Comet Assay or single cell gel ...
Highlights: • Aging process increases ROS accumulation. • Aging process increases DNA damage levels. • Absence of SOD activity does not cause DNA damage in young cells. • Absence of SOD activity accelerate aging and increase oxidative DNA damages during the aging process. - Abstract: Superoxide dismutases (SOD) serve as an important antioxidant defense mechanism in aerobic organisms, and deletion of these genes shortens the replicative life span in the budding yeast Saccharomyces cerevisiae. Even though involvement of superoxide dismutase enzymes in ROS scavenging and the aging process has been studied extensively in different organisms, analyses of DNA damages has not been performed for replicatively old superoxide dismutase deficient cells. In this study, we investigated the roles of SOD1, SOD2 and CCS1 genes in preserving genomic integrity in replicatively old yeast cells using the single cell comet assay. We observed that extend of DNA damage was not significantly different among the ...
TY - JOUR. T1 - DNA damage repair and telomere length in normal breast, preneoplastic lesions, and invasive cancer. AU - Raynaud, Christophe M.. AU - Hernandez, Juana. AU - Llorca, Frédérique P.. AU - Nuciforo, Paolo. AU - Mathieu, Marie Christine. AU - Commo, Frederic. AU - Delaloge, Suzette. AU - Sabatier, Laure. AU - André, Fabrice. AU - Soria, Jean Charles. PY - 2010/8/1. Y1 - 2010/8/1. N2 - Objectives: Carcinogenesis is a multistep process involving the accumulation of genetic and molecular abnormalities. It has been suggested that there is a relationship between telomere attrition in the early stages of carcinogenesis and activation of the DNA damage response machinery. We explored telomere length modification and damage response pathway activation at 3 steps of breast carcinogenesis. Methods: We carried out a retrospective immunohistochemical analysis of pathway ataxia telangiectasia mutated (p-ATM) (series 1981) and +-H2AX (series 139) levels in normal breast, preneoplastic lesions, ...
In every cell cycle, DNA accumulates lesions that impair the advance of the replication forks. Eventually, this leads to an accumulation of single‐stranded DNA (ssDNA), which activates a number of mechanisms aimed at ensuring that DNA replication passes through DNA lesions and repairing the gaps. Defects in this response cause replication fork stalling and genetic instability in yeast (Vázquez et al, 2008; Putnam et al, 2010) and are associated with cancer in humans (Moynahan and Jasin, 2010). This DNA damage tolerance (DDT) response relies in error‐prone translesion synthesis (TLS) and error‐free template switch (TS) mechanisms. TLS fills the gap by extending the 3′‐end past the damaged template, using specialized DNA polymerases that are able to incorporate a nucleotide opposite the lesion, while TS uses the information of the sister chromatid to bypass damage (Friedberg, 2005). A crucial protein in this decision is the DNA polymerase processivity factor PCNA, which functions as a ...
The rates at which lesions are removed by DNA repair can vary widely throughout the genome, with important implications for genomic stability. To study this, we measured the distribution of nucleotide excision repair (NER) rates for UV-induced lesions throughout the budding yeast genome. By plotting these repair rates in relation to genes and their associated flanking sequences, we reveal that, in normal cells, genomic repair rates display a distinctive pattern, suggesting that DNA repair is highly organized within the genome. Furthermore, by comparing genome-wide DNA repair rates in wild-type cells and cells defective in the global genome-NER (GG-NER) subpathway, we establish how this alters the distribution of NER rates throughout the genome. We also examined the genomic locations of GG-NER factor binding to chromatin before and after UV irradiation, revealing that GG-NER is organized and initiated from specific genomic locations. At these sites, chromatin occupancy of the histone ...
Following DNA damage, mRNA levels decrease, reflecting a coordinated interaction of the DNA repair, transcription and RNA processing machineries. In this study, we provide evidence that transcription and polyadenylation of mRNA precursors are both affected in vivo by UV treatment. We next show that the polyadenylation factor CstF, plays a direct role in the DNA damage response. Cells with reduced levels of CstF display decreased viability following UV treatment, reduced ability to ubiquitinate RNA polymerase II (RNAP II), and defects in repair of DNA damage. Furthermore, we show that CstF, RNAP II and BARD1 are all found at sites of repaired DNA. Our results indicate that CstF plays an active role in the response to DNA damage, providing a link between transcription-coupled RNA processing and DNA repair.
Investigating the cellular and molecular signatures in eukaryotic cells following exposure to nanoparticles will further our understanding on the mechanisms mediating nanoparticle induced effects. This study illustrates the molecular effects of silver nanoparticles (Ag-np) in normal human lung cells, IMR-90 and human brain cancer cells, U251 with emphasis on gene expression, induction of inflammatory mediators and the interaction of Ag-np with cytosolic proteins. We report that silver nanoparticles are capable of adsorbing cytosolic proteins on their surface that may influence the function of intracellular factors. Gene and protein expression profiles of Ag-np exposed cells revealed up regulation of many DNA damage response genes such as Gadd 45 in both the cell types and ATR in cancer cells. Moreover, down regulation of genes necessary for cell cycle progression (cyclin B and cyclin E) and DNA damage response/repair (XRCC1 and 3, FEN1, RAD51C, RPA1) was observed in both the cell lines. Double strand
Cell proliferation demands that the cells go through the mitotic cell cycle, involving duplication of their DNA before chromosome segregation and cell division. During G1 phase the decision is made whether to start a new round of the cell cycle, go into a quiescent state or enter into meiosis. It is critical for the cells to carefully regulate the progression through G1 phase, where the cells become committed to a new round in the cell cycle. Cell cycle progression is negatively regulated by checkpoint mechanisms to make sure that the events of one cell cycle phase have been completed before continuing to the next phase. Checkpoints delay the cell cycle in response to several forms of stress. DNA damage checkpoints are thought to allow additional time for DNA repair before DNA replication (S phase) and before chromosome segregation (mitosis). These responses are crucial for the cells to maintain their genetic integrity. The fact that the majority of cancer cells have defects in G1-S checkpoints ...
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Activating transcription factor 2 (ATF2) is regulated by JNK/p38 in response to stress. Here, we demonstrate that the protein kinase ATM phosphorylates ATF2 on serines 490 and 498 following ionizing radiation (IR). Phosphoantibodies to ATF2(490/8) reveal dose- and time-dependent phosphorylation of ATF2 by ATM that results in its rapid colocalization with gamma-H2AX and MRN components into IR-induced foci (IRIF). Inhibition of ATF2 expression decreased recruitment of Mre11 to IRIF, abrogated S phase checkpoint, reduced activation of ATM, Chk1, and Chk2, and impaired radioresistance. ATF2 requires neither JNK/p38 nor its DNA binding domain for recruitment to IRIF and the S phase checkpoint. Our findings identify a role for ATF2 in the DNA damage response that is uncoupled from its transcriptional activity. ...
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The nucleotide excision repair (NER) pathway operates through two sub-pathways: global genome repair (ggNER) and transcription-coupled repair (TCR) or gene- and strand-specific DNA repair [1, 2, 4]. The ggNER is a repair mechanism which has the ability to repair DNA damage to the overall genome with equivalent efficiency. In contrast, TCR is a kind of heterogeneous DNA repair, where repair to the damaged DNA in the status of transcription activity is superior to the silenced genes and the repair of the transcribed strand is superior to the untranscribed strand. Some DNA repair proteins and transcription factors have been identified to be involved in TCR such as CSA, CSB, XPG, XAB2, RNA polymerase II, and TFIIH [1, 7, 8, 24]. Blockage of RNA polymerase □ at the DNA damage site is believed to create a conducive environment for DNA repair [7, 9]. In this report, we provide evidence to demonstrate that DNA-PKcs, a known critical component in the NHEJ pathway of DNA double-strand breaks, is also ...
... s are capable of a DNA damage response that is a critical mechanism for maintaining genome stability.[64] The DNA damage ... DNA damage and repair. Plants are continuously exposed to a range of biotic and abiotic stresses. These stresses often cause ... Yoshiyama, K.O. (2016). "SOG1: a master regulator of the DNA damage response in plants". Genes and Genetic Systems. 90 (4): 209 ... Roldán-Arjona, T.; Ariza, R.R. (2009). "Repair and tolerance of oxidative DNA damage in plants". Mutation Research. 681 (2-3): ...
Splicing response to DNA damage[edit]. DNA damage affects splicing factors by altering their post-translational modification, ... DNA damage often disrupts splicing by interfering with its coupling to transcription. DNA damage also has an impact on the ... DNA damages modulate the alternative splicing of the DNA repair genes Brca1 and Ercc1. ... "The RNA Splicing Response to DNA Damage". Biomolecules. 5 (4): 2935-77. doi:10.3390/biom5042935. PMC 4693264. PMID 26529031.. ...
DNA damage and repair[edit]. Several bacterial species have been shown to accumulate DNA damages upon desiccation. Deinococcus ... The chromosomal DNA from desiccated D. radiodurans revealed increased DNA double-strand breaks.[4] DNA double-strand breaks are ... Upon exposure to extreme dryness, Bacillus subtilis endospores acquire DNA-double strand breaks and DNA-protein crosslinks.[6] ... DNA Repair (Amst.). 6 (9): 1271-6. doi:10.1016/j.dnarep.2007.02.009. PMID 17360246.. ...
DNA damage is considered to be the primary cause of cancer.[9][10] More than 60,000 new naturally occurring DNA damages arise, ... Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking. ... As one example of an exogenous carcinogeneic agent, tobacco smoke causes increased DNA damage, and these DNA damages likely ... Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage ...
Sperm DNA damage[edit]. Sperm DNA damage is common in infertile men.[6] About 31% of men with sperm motility defects have high ... Simon L, Lutton D, McManus J, Lewis SE (2011). "Sperm DNA damage measured by the alkaline Comet assay as an independent ... "Which isolated sperm abnormality is most related to sperm DNA damage in men presenting for infertility evaluation". J. Assist. ...
DNA damage is very common. Naturally occurring DNA damages (mostly due to cellular metabolism and the properties of DNA in ... Bernstein C, Prasad AR, Nfonsam V, Bernstei H (2013). "DNA Damage, DNA Repair and Cancer". New Research Directions in DNA ... Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking.[ ... also see article DNA damage (naturally occurring) ]. Additional DNA damages can arise from exposure to exogenous agents. ...
DNA damage reduces fertility in male sperm, as caused by oxidative DNA damage,[30] smoking,[27] other xenobiotic DNA damaging ... DNA damage *DNA damage reduces fertility in female ovocytes, as caused by smoking,[27] other xenobiotic DNA damaging agents ( ... or other DNA damaging agents including reactive oxygen species, fever or high testicular temperature.[32] The damaged DNA ... "Impact of DNA damage on the frequency of sperm chromosomal aneuploidy in normal and subfertile men". Iran. Biomed. J. 15 (4): ...
Damage to a cell's DNA is particularly harmful because DNA is the blueprint for protein production and unlike other molecules ... The vulnerability of post-mitotic neurons to DNA damage (such as oxidative lesions or certain types of DNA strand breaks), ... "DNA Damage, DNA Repair, Aging, and Neurodegeneration". Cold Spring Harb Perspect Med. 5 (10): a025130. doi:10.1101/cshperspect. ... Increased oxidative DNA damage in the brain is associated with Alzheimer's disease and Parkinson's disease.[17] Defective DNA ...
It has been suggested that Direct DNA damage be merged into this article. (Discuss) Proposed since January 2021. ... DNA repair[edit]. Further information: DNA repair and ultraviolet light and cancer ... "DNA Damage and Repair". Nature. 421 (6921): 436-439. Bibcode:2003Natur.421..436F. doi:10.1038/nature01408. PMID 12540918.. ... Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions.[1][2] ...
DNA repair is effective at removing DNA damages.[16] However, in spermatogenesis the ability to repair DNA damages decreases ... However, errors in maternal DNA repair of sperm DNA damage can result in zygotes with chromosomal structural aberrations. ... DNA damage during spermatogenesis[edit]. During the mitotic and meiotic cell divisions of mammalian gametogenesis, ... Such sperm DNA damage can be transmitted unrepaired into the egg where it is subject to removal by the maternal repair ...
4) Protection against DNA damage. Mild, transient scrotal heat stress causes DNA damage, reduced fertility and abnormal ... Paul C, Murray AA, Spears N, Saunders PT (2008). "A single, mild, transient scrotal heat stress causes DNA damage, subfertility ... The gametes contain DNA for fertilization of an ovum[2]. *Sertoli cells - the true epithelium of the seminiferous epithelium, ... external location of the testicles provides the adaptive benefit of protecting spermatogenic cells from heat-induced DNA damage ...
These compounds mutate DNA strands and produce genetic damage, inducing newly lysis and subsequent cell death. Its action on ... DNA damage. Cancer, particularly leukemia. Leukopenia. Growth reduction. Reproductive deficiencies: sterility, reduction in ... D. radiodurans is capable to resist oxidative stress and DNA damage from radiation, and reduces technetium, uranium and ... This effect is accentuated if the absorbed dose is between 0.5 and 2 Sv, in whose first damage, nausea and hair loss are ...
In DNA, this causes lasting damage. DNA is also indirectly damaged by reactive oxygen species produced by ultraviolet A (UVA), ... which has energy too low to damage DNA directly. This is why ultraviolet at all wavelengths can damage DNA, and is capable of ... With UVB, the damage to DNA becomes direct, with photochemical formation of pyrimidine dimers. ... Visible light is able to affect a few molecules with single photons, but usually not in a permanent or damaging way, in the ...
... disorder is associated with reduced expression of specific DNA repair enzymes and increased levels of oxidative DNA damages.[54 ... "DNA Damage in Major Psychiatric Diseases". Neurotox Res. 30 (2): 251-67. doi:10.1007/s12640-016-9621-9. PMC 4947450. PMID ...
Cell damage, including direct DNA damage. *Lisfranc injury. *Tracheobronchial injury. *Eye injury *Chemical eye injury ... it specifically refers to a sharp injury which damages the dermis of the skin. ...
Damage-related factors[edit]. *DNA damage theory of ageing: DNA damage is thought to be the common basis of both cancer and ... DNA oxidation and caloric restriction: Caloric restriction reduces 8-OH-dG DNA damage in organs of ageing rats and mice.[119][ ... Genetic damage (aberrant structural alterations of the DNA), mutations (changes in the DNA sequence), and epimutations ( ... Gensler, Helen L.; Bernstein, Harris (1981). "DNA Damage as the Primary Cause of Aging". The Quarterly Review of Biology. 56 (3 ...
Actively transcribed regions of DNA often form R-loops that are vulnerable to DNA damage. Introns reduce R-loop formation and ... DNA replication. References[edit]. *^ Thomas M, White RL, Davis RW (July 1976). "Hybridization of RNA to double-stranded DNA: ... R-loops, Introns and DNA damage[edit]. Introns are non-coding regions within genes that are transcribed along with the coding ... When unscheduled R-loops form, they can cause damage by a number of different mechanisms.[20] Exposed single-stranded DNA can ...
DNA damage can also cause epigenetic changes.[27][28][29] DNA damage is very frequent, occurring on average about 60,000 times ... see DNA damage (naturally occurring)). These damages are largely repaired, but at the site of a DNA repair, epigenetic changes ... Bacteria also use DNA adenine methylation (rather than DNA cytosine methylation) as an epigenetic signal. DNA adenine ... "DNA damage, homology-directed repair, and DNA methylation". PLoS Genet. 3 (7): e110. PMC 1913100 . PMID 17616978. doi:10.1371/ ...
Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms,[58][59] while damage to ... protect DNA from oxidative stress. It has been proposed that polymorphisms in these enzymes are associated with DNA damage and ... Oxidative damage in DNA can cause cancer. Several antioxidant enzymes such as superoxide dismutase, catalase, glutathione ... Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J (November 2004). "Role of oxygen radicals in DNA damage and cancer incidence ...
"Alcohol induces DNA damage and the Fanconi anemia D2 protein implicating FANCD2 in the DNA damage response pathways in brain". ... cause DNA damage in the brain. During repair of DNA damages some individual repair events may alter the acetylations of ... de Souza MF, Gonçales TA, Steinmetz A, Moura DJ, Saffi J, Gomez R, Barros HM (April 2014). "Cocaine induces DNA damage in ... Johnson Z, Venters J, Guarraci FA, Zewail-Foote M (June 2015). "Methamphetamine induces DNA damage in specific regions of the ...
... all cause DNA damage in the brain. During repair of DNA damages some individual repair events can alter the methylation of DNA ... "Alcohol induces DNA damage and the Fanconi anemia D2 protein implicating FANCD2 in the DNA damage response pathways in brain". ... Modification of DNA[edit]. In eukaryotes, the accessibility of large regions of DNA can depend on its chromatin structure, ... de Souza MF, Gonçales TA, Steinmetz A, Moura DJ, Saffi J, Gomez R, Barros HM (April 2014). "Cocaine induces DNA damage in ...
DNA damages being the driving force of aging. (Also see DNA damage theory of aging). FANCG has been shown to interact with ... The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks. The FA proteins ... Park JY, Zhang F, Andreassen PR (2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". ... DNA interstrand crosslinks are highly deleterious damages that are repaired by homologous recombination involving coordination ...
Basu, A. (2010). "Cellular Responses to Cisplatin-Induced DNA Damage". Journal of Nucleic Acids. 2010: 1-16. doi:10.4061/2010/ ... Huang M, Krepkiy D, Hu W, Petering D (2004). "Zn-, Cd-, and Pb-transcription factor IIIA: properties, DNA binding, and ...
S and G2 phase to check if DNA is normal, and withdraws the cell from cycle if the DNA is damaged or has undergone incomplete ... Another type of negative regulator is p53, which halts the cell cycle process upon detection of DNA damage so as to provide to ... This regulator can also induce apoptosis when the DNA damage is too large and cannot be repaired. Checkpoints in cell cycles ... The withdrawal process also prevents diseased cells, or cells with mutated or damaged DNA, from continuing to divide and ...
... (TS) plays a crucial role in the early stages of DNA biosynthesis. DNA damage or deletion occur on a daily ... Both cause DNA damage. The following reaction is catalyzed by thymidylate synthase: 5,10-methylenetetrahydrofolate + dUMP ⇌ {\ ... The enzyme is essential for regulating the balanced supply of the 4 DNA precursors in normal DNA replication: defects in the ... Therefore, synthesis and insertion of healthy DNA is vital for normal body functions and avoidance of cancerous activity. In ...
DNA Damage and Repair. Contemporary Cancer Research. pp. 107-124. doi:10.1007/978-1-59259-095-7_5 (inactive 2021-01-20). ISBN ... The coding sequence is on the Crick strand of the DNA. YDL102W (aka POL3 encoding a subunit of DNA polymerase delta) is located ... and are significant tools in the study of DNA damage and repair mechanisms. S. cerevisiae has developed as a model organism ... reactive oxygen species increase leading to the accumulation of DNA damages such as apurinic/apyrimidinic sites and double- ...
"Benzophenone Photosensitized DNA Damage". Acc. Chem. Res. 45 (9): 1558-1570. doi:10.1021/ar300054e. PMID 22698517. Doug Brunk ( ... The interaction with DNA and the successive photo-induced energy transfer is at the base of the benzophenone activity as a DNA ... Benzophenone prevents ultraviolet (UV) light from damaging scents and colors in products such as perfumes and soaps. ... From a molecular chemistry point of view interaction of benzophenone with B-DNA has been demonstrated experimentally. ...
"Cancer and Aging as Consequences of Unrepaired DNA Damage". In Kimura, Honoka; Suzuki, Aoi. New Research on DNA Damages. New ... Oxidative DNA damage 8-hydroxydeoxyguanosine in houseflies was found in one study to increase with age and reduce life ... Holmes, G. E.; Bernstein, C.; Bernstein, H. (September 1992). "Oxidative and other DNA damages as the basis of aging: a review ... "DNA oxidative damage and life expectancy in houseflies". PNAS. 91 (25): 12332-5. Bibcode:1994PNAS...9112332A. doi:10.1073/pnas. ...
reported that even though the DNA damage detected after MRI was at a level comparable to that produced by scans using ionizing ... "Is cardiac magnetic resonance imaging causing DNA damage?". European Heart Journal. 34 (30): 2337-2339. doi:10.1093/eurheartj/ ... The strong static magnetic field can cause damage by pulling in nearby heavy metal objects converting them to projectiles.[84] ... differences in the mechanism by which this damage takes place suggests that the cancer risk of MRI, if any, is unknown.[91] ...
... and also increase DNA damage.[38] Mice fed a diet with added DCA mimicking colonic DCA levels in humans on a high fat diet ...
... based on morphological and DNA sequence comparisons, Chalara fraxinea was suggested to be the asexual stage (anamorph) of the ... In 2009 it was estimated that 50 per cent of Denmark's ash trees were damaged by crown-dieback,[21] and a 2010 estimate stated ... perforating the middle lamella but damage to either the plasmalemma or cell walls was not observed.[29] The disease is often ...
Dysfunction of lamin A triggers a DNA damage response and cellular senescence. DNA Repair (Amst.). 2006, 5 (2): 286-9. PMID ...
This method was also used in Meselson and Stahl's famous experiment in which they proved that DNA replication is semi- ... Buffered - neutral pH, preventing damage to the structure of proteins including enzymes (which could affect ionic bonds) ... They used density gradient centrifugation to determine which isotope or isotopes of nitrogen were present in the DNA after ...
This damages their ability to aerate the soil. Living roots drill millions of tiny holes in the soil and thus provide oxygen. ... "Masanobu Fukuoka: The man who did nothing By Malvika Tegta" "DNA Daily News and Analysis". "Published: Sunday, Aug 22, 2010, 2: ...
Competence in S. pneumoniae is induced by DNA-damaging agents such as mitomycin C, fluoroquinolone antibiotics (norfloxacin, ... The ability of S. pneumoniae to repair the oxidative DNA damages in its genome, caused by this host defense, likely contributes ... On the basis of these findings, they suggested that transformation is an adaptation for repairing oxidative DNA damages. S. ... a key component of the recombinational repair machinery for removing DNA damages. ...
This damage occurs due to the synthesis of Ebola virus glycoprotein (GP), which reduces the availability of specific integrins ... December 1999). "Identification of Ebola virus sequences present as RNA or DNA in organs of terrestrial small mammals of the ... responsible for cell adhesion to the intercellular structure and causes liver damage, leading to improper clotting. The ...
DNA studies also suggest an unknown degree of interbreeding between Homo sapiens sapiens and Homo sapiens denisova.[27] ... and that the damage to recovered human bones was either the result of excarnation or predation by carnivores such as saber- ... Evidence from canine DNA collected by Robert K. Wayne suggests that dogs may have been first domesticated in the late Middle ... Chimpanzees are the closest to humans genetically, sharing more than 96% of their DNA code with humans, and their digestive ...
... a genetic mismatch as small as a single DNA base pair is significant so perfect matches require knowledge of the exact DNA ... Unlike other organs, bone marrow cells can be frozen (cryopreserved) for prolonged periods without damaging too many cells. ... first European bone marrow transplant in November 1958 on five Yugoslavian nuclear workers whose own marrow had been damaged by ...
DNA construct. *DNA damage theory of ageing. *DNA methylation. *DNA polymerase. *DNA repair ... Pages in category "DNA". The following 33 pages are in this category, out of 33 total. ... Retrieved from "https://simple.wikipedia.org/w/index.php?title=Category:DNA&oldid=4367965" ...
... presence of DNA damage).[13] ... The longest subsystem cascade is DNA replication. In ... "DnaA couples DNA replication and the expression of two cell cycle master regulators". The EMBO Journal. 25 (2): 346-56. doi ... Caulobacter cells, replication of the chromosome involves about 2 million DNA synthesis reactions for each arm of the ...
DNA Plant Technology (DNAP), Agritope and Monsanto developed tomatoes that delayed ripening by preventing the production of ... The fruits produced were not visibly damaged after being stored at room temperature for 45 days, whereas unmodified tomatoes ... damage in the laboratory, greenhouse and field". Crop Protection. 23 (2): 135-139. doi:10.1016/j.cropro.2003.08.006.. ...
... and may damage young living trees. One of the most common and widely distributed borer species in North America is the ... but recent research into DNA sequences suggests that this interpretation leaves the Pinales without Taxales as paraphyletic, ... for fear of increased danger of frost damage to succulent tissues. A presentation at the North American Forest Tree Nursery ...
Their DNA is slightly less than one percent different from humans, and they age at a much slower rate. Since ninety-seven ... The call reveals that they do not have enough fuel to do any more damage to Washington and her demands to Martinez were a bluff ... President Martinez becomes suspicious of his wife's refusal to take the DNA test. Vice President Jarvis meets Sophia with a ... when it's actually a ruse to gather DNA of possible 'sleepers,' much to his wife's disapproval and leading Martinez to question ...
The examination of preserved museum specimens has found Borrelia DNA in an infected Ixodes ricinus tick from Germany that dates ... Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response,[96] a ... Except for one study in Europe,[229] much of the data implicating lizards is based on DNA detection of the spirochete and has ... In dogs, a serious long-term prognosis may result in glomerular disease,[278] which is a category of kidney damage that may ...
... proteins and lipids from oxidative damage (ID 1647), "cardiovascular system" (ID 1844), "mental state and performance" (ID 1845 ... "Scientific Opinion on the substantiation of health claims related to quercetin and protection of DNA, ...
Early DNA-analysis showed that the Capparaceae-as defined at that moment-were paraphyletic, and it was suggested to assign the ... When the cell is damaged, the myrosinases hydrolise the glucosinolates, leading to the synthesis of isothiocyanates, which are ... Current insights in the relationships of the Brassicaceae, based on a 2012 DNA-analysis, are summarized in the following tree.[ ... is one of the most aggressive and damaging invasive species in North America. Invasive aggressive mustard species are known for ...
Bernstein H, Byerly HC, Hopf FA, Michod RE (September 1985). "Genetic damage, mutation, and the evolution of sex". Science. 229 ... Gilbert DA, Packer C, Pusey AE, Stephens JC, O'Brien SJ (1991-10-01). "Analytical DNA fingerprinting in lions: parentage, ...
Polar bear attacks on belugas and narwhals are usually successful in winter, but rarely inflict any damage in summer.[80] ... "More DNA support for a Cetacea/Hippopotamidae clade: the blood-clotting protein gene gamma-fibrinogen" (PDF). Molecular ... which shrink as they surface to prevent damage), slightly flattened corneas and a tapetum lucidum; these adaptations allow for ...
Jan Ullrich - DNA tests confirmed that the 9 bags that were marked Jan, number 1 or Hijo Rudicio (Son of Rudy) all contained ... Mark Kreidler, Ullrich may be free, but damage is done, ESPN.com, 27 October 2006 ... He hoped teams would require cyclists to submit DNA samples to clear their names.[26] The investigations into Spanish riders ... matched Jan Ullrich's saliva DNA.[4] On 7 May, Basso admitted involvement with the scandal to the Italian National Olympic ...
"Same DNA deletion paves paths to autism, schizophrenia , Spectrum". Spectrum. 2016-10-18. Retrieved 2016-11-13.. ... damaged organs, strokes, high blood pressure, and loss of vision. Sickle red blood cells also have a shortened lifespan and die ...
"Sister group relationship of turtles to the bird-crocodilian clade revealed by nuclear DNA-coded proteins". Molecular Biology ... and protect their brains against damage by struggling prey). Skinks (family Scincidae) also have evolved a bony secondary ...
Repetitive DNA sequences must be blocked by adding short fragments of DNA to the sample. The probe is then applied to the ... Cell damage. *Wound healing. Cellular adaptation. Atrophy. Hypertrophy. Hyperplasia. Dysplasia. Metaplasia Squamous. Glandular ... Preparation and hybridization process - DNA[edit]. Scheme of the principle of the FISH Experiment to localize a gene in the ... Preparing DNA probes for one species and performing FISH with this probe allows one to visualize the distribution of this ...
... as well as damage to a chemical plant and three nearby villages.[citation needed] The 1984 Bhopal disaster in India resulted in ... Chemical engineering principles were used to produce DNA sequences in large quantities.[28] ...
The DNA in a donated ovum can be removed and replaced with the DNA of the receiver. Further in the future, stem cell ... Doctors plan uterus transplants to help women with removed, damaged wombs have babies. Associated Press. ...
These proteins tightly bind and condense the DNA, and are in part responsible for resistance to UV light and DNA-damaging ... Finally, DNA repair enzymes contained within the endospore are able to repair damaged DNA during germination. ... The DNA is replicated and a membrane wall known as a spore septum begins to form between it and the rest of the cell. The ... The dipicolinic acid helps stabilize the proteins and DNA in the endospore.[14]:141 Next the peptidoglycan cortex forms between ...
This is due to the accumulation of oxidative damage to DNA by aging and cellular metabolic activity and the shortening of ...
cellular response to DNA damage stimulus. • heart looping. • blood vessel development. • membrane protein ectodomain ... positive regulation of transcription, DNA-templated. • heart development. • negative regulation of axonogenesis. • embryonic ...
BaP was shown to cause genetic damage in lung cells that was identical to the damage observed in the DNA of most malignant lung ... Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 ... Interaction with DNA[edit]. Metabolism of benzo[a]pyrene yielding the carcinogenic benzo[a]pyren-7,8-dihydrodiol-9,10-epoxide. ... by confusing the double-helical DNA structure. This disrupts the normal process of copying DNA and causes mutations, which ...
This helps to protect the organism from a lethal overactivation of the immune system, and minimizes tissue damage from ... "Bdnf DNA methylation modifications in the hippocampus and amygdala of male and female rats exposed to different caregiving ... Glucocorticoids have many important functions, including modulation of stress reactions, but in excess they can be damaging. ...
Editorial: DNA damage & immunity.. Garinis GA1, Schwer B2, Schumacher B3. ...
... their bodies might have less capacity to repair everyday damage to cells DNA, a small study hints. ... "But they didnt link shift work to actual DNA damage," Reid said. And its not really clear, she added, how melatonin fits in. ... He explained that 8-OH-dG is excreted in the urine when the body repairs DNA damage that occurs during normal body processes. ... home/sleep center/ sleep a-z list/ could shift work damage your dna? article ...
DNA damage, DNA repair, DNA Repair, Congresses, DNA Damage ... DNA damage by Biochemical Society (Great Britain). Symposium; 1 ... DNA damage from causes to cures organised and edited by Richard P. Bowater, Rhonda H. Borts and Malcolm F. White Published 2009 ... Based on papers presented at the 2008 Biochemical Society Annual Symposium entitled "DNA damage: from causes to cures", held at ... Citation ,publisher = Portland Press ,ol = 24382592M ,isbn = 9781855781733 ,publication-place = London ,title = DNA damage , ...
Regulation of the DNA damage response is tightly connected to transcription and replication. These DNA transacting processes ... DNA damage repair: anytime, anywhere?. Essers J1, Vermeulen W, Houtsmuller AB. ... Currently, quantitative live cell imaging techniques combined with methods to induce local DNA damage in a small region of the ... However, unlike replication and transcription, DNA repair systems may be required anywhere, and at any time, whenever DNA ...
They indicate that damage to DNA can lead to cancer and hence one should be... ... Setlow R.B. (1981) DNA Damage and Carcinogenesis. In: Seeberg E., Kleppe K. (eds) Chromosome Damage and Repair. NATO Advanced ... They indicate that damage to DNA can lead to cancer and hence one should be concerned about environmental agents that react ... Nevertheless, there are arguments against this point of view (1) and, even if damage to DNA is the important element in cancer ...
Host DNA damage response factors localize to merkel cell polyomavirus DNA replication sites to support efficient viral DNA ... In response to any source of DNA damage, cells must initiate an effective DNA damage response (DDR) to maintain genomic ... Viral DNA replication-dependent DNA damage response activation during bk polyomavirus infection. J Virol, 89: 5032-5039. ... The DNA damage response: Making it safe to play with knives. Mol Cell, 40: 179-204.CrossRefPubMedCentralPubMedGoogle Scholar ...
DNA replication and DNA repair. In humans, the UV-damaged DNA-binding protein (UV-DDB) complex detects UV-light-induced ... cryo-electron microscopy structures of UV-DDB bound to nucleosomes bearing a 6-4 pyrimidine-pyrimidone dimer or a DNA-damage ... We find that UV-DDB binds UV-damaged nucleosomes at lesions located in the solvent-facing minor groove without affecting the ... Cryo-electron microscopy structures reveal that the DNA-repair factor UV-DDB exposes inaccessible nucleosome lesions for ...
Scientists are warning that a water treatment widely used in developing countries could be damaging the DNA of those drinking ... Common water treatments could damage DNA. University of East Anglia. Journal. Environmental Health. Keywords. *DEVELOPING ... Scientists are warning that a water treatment widely used in developing countries could be damaging the DNA of those drinking ... But this study brings together a body of work which shows it is potentially damaging DNA, and harming reproductive success." ...
DNA damage and oxidative DNA repair were also significantly greater in lymphocytes of applicators and farm workers.. ... Lymphocytes were analyzed for oxidative DNA repair activity and DNA damage (Comet assay), and was serum analysed for lipid ... Oxidative stress and DNA damage in agricultural workers. Informaci n bibliogr fica. 2nd Quarter 2009, Vol.14, No.2, p.206-214. ... Cellular DNA damage was validated using lymphocyte cell cultures. Compared to unexposed populations, urinary OP metabolites ...
... chemical book of DNA. Now Japanese researchers have shown how environmentally damaged letters lead to transcription flaws and, ... When lurking in the area during DNA replication, it bonds with adenine and causes the latter to pair with thymine rather than ... Subtle changes in the pairing of the chemical letters of DNA--adenine, cytosine, guanine and thymine--produce new cells with ... And that means Nakabeppu and his colleagues may have shown how environmental damage leads to cellular mutation, for good and ...
... and functional aspects of DNA and RNA research. ... involves DNA damage and p53 is also involved in DNA damage ... The DNA damage response is transduced mainly via p53 and c-Abl. Cisplatin-induced DNA damage activates p53, leading to the ... it stalls cell proliferation by inhibiting DNA synthesis, followed by activation of DNA damage response. [. 5. ]. Cisplatin-DNA ... suggesting alternate pathways of sensing cisplatin-induced DNA damage.. 6.2. c-Abl and Cisplatin-Induced DNA Damage Response. ...
Cells respond to DNA damage by activating a complex network of the so-called checkpoint pathways to delay their cell-cycle ... Checking on DNA damage in S phase Nat Rev Mol Cell Biol. 2004 Oct;5(10):792-804. doi: 10.1038/nrm1493. ... Cells respond to DNA damage by activating a complex network of the so-called checkpoint pathways to delay their cell-cycle ... the signalling pathways and the spatio-temporal organization of the intra-S-phase DNA-damage checkpoint and its impact on the ...
The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and ... contributing to tolerance of DNA damage. A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key ... The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating ... recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, ...
... the effects of the potentially game-changing gene editing tool CRISPR/Cas9 have found it can cause unexpected genetic damage ... CRISPR/Cas9, one of the newest genome editing tools, can alter sections of DNA in cells by cutting at specific points and ... "We found that changes in the DNA have been seriously underestimated before now," said Allan Bradley, a professor at Britains ... "to verify that the alterations to the DNA sequence are those, and only those, that had been designed to occur". ...
Yellow staining shows trapping of the PARP enzyme at a site of DNA damage. ... Microscopic images of a breast cancer cell with DNA damage. Left, six hours after treatment with either the epigenetic agent ... Microscopic images of a breast cancer cell with DNA damage. Left, six hours after treatment with either the epigenetic agent ... Yellow staining shows trapping of the PARP enzyme at a site of DNA damage. ...
Oxidative DNA Damage to Sperm Cells and Peripheral Blood Leukocytes in Infertile Men. BACKGROUND Oxidative DNA damage is ... Sperm DNA damage measured by sperm chromatin structure assay in men with a history of undescended testes. The aim of this study ... Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling. Cell division cycle 6 ... DNA damage response in cisplatin-induced nephrotoxicity. Cisplatin and its derivatives are widely used chemotherapeutic drugs ...
It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatch repair are resistant ... or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. The absence of a par … ... DNA mismatch repair is an important pathway of mutation avoidance. ... DNA damage tolerance, mismatch repair and genome instability Bioessays. 1994 Nov;16(11):833-9. doi: 10.1002/bies.950161110. ...
... research now demonstrates what triggers the damage to your cells. ... research now demonstrates what triggers the damage to your ... Ketan Patel commented on the extent of the damage their data revealed, saying:11 "We saw huge amounts of DNA damage in these ... "Some cancers develop due to DNA damage in stem cells. While some damage occurs by chance, our findings suggest that drinking ... Since alcohol is a carbohydrate, it not only damages your liver and raises levels of DNA-damaging acetaldehyde, but it also ...
A network comparison of genetic interactions mapped at two conditions reveals genetic responses to DNA damage in yeast. ... A network comparison of genetic interactions mapped at two conditions reveals genetic responses to DNA damage in yeast. ...
The causal role of oxidative DNA damage in aging is strongly supported in a study by de Boer et al. (see the Perspective by ... The authors propose that the aging phenotype in the TTD mice is caused by unrepaired DNA damage that compromises transcription ... showed greatly accelerated aging that correlated with an increased cellular sensitivity to oxidative DNA damage. ... A popular theory postulates that aging is triggered by cellular accumulation of oxidative damage. ...
... absence of DNA damage) p53 is expressed at low levels" he says. "The close relationship between p53 activation and DNA damage ... "DNA Damage Induced by Multi-walled Carbon Nanotubes in Mouse Embryonic Stem Cells"), the DNA damage induced by MWCNTs was ... In the presence of damaged DNA for instance, the p53 protein is activated by protein phosphorylation as a master guardian that ... "Enhanced expression of p53 may also trigger cell death by apoptosis if the DNA damage is beyond repair, while under normal ...
Particularly damaging to our cellular DNA are the particles from the underground system in Stockholm, Sweden, according to a ... Underground air might cause DNA damage. 15.12.2006. Our everyday environments are full of airborne particles that are harmful ... Free radicals are highly reactive molecules that can prove harmful to the cells DNA; although such damage can often be ... The damage is caused when these particles enter the body and form free radicals in the bodys cells. ...
DNA Damage Signaling Pathway RT2 Profiler PCR Array The Rat DNA Damage Signaling RT² Profiler PCR Array profiles the expression ... DNA Damage Signaling Pathway RT2 Profiler PCR Array The Human DNA Damage Signaling RT² Profiler PCR Array profiles the ... DNA Damage Signaling Pathway RT2 Profiler PCR Array The Mouse DNA Damage Signaling RT² Profiler PCR Array profiles the ... DNA Damage Signaling Pathway EpiTect ChIP qPCR Array The Human DNA Damage Signaling Pathway EpiTect ChIP qPCR Array profiles ...
Signalling DNA Damage. By Andres Joaquin Lopez-Contreras and Oscar Fernandez-Capetillo ... Andres Joaquin Lopez-Contreras and Oscar Fernandez-Capetillo (September 6th 2012). Signalling DNA Damage, Protein ... Andres Joaquin Lopez-Contreras and Oscar Fernandez-Capetillo (September 6th 2012). Signalling DNA Damage, Protein ... www.intechopen.com/embed/protein-phosphorylation-in-human-health/signalling-dna-damage /,. Embed this code snippet in the HTML ...
... which means whatever happened during the US-led war is still there and the damage has been done to DNA, says Chris Busby a ... Damage done to DNA cant be cleaned up. "The problem is not that there are these contamination sites. It is very difficult to ... Fallujah battle toxic legacy: Damage done to DNA Christopher Busby is an expert on the health effects of ionizing radiation. ... The problem is that the damage that has been done to the DNA - you cant clean that up. The continuing level of congenital ...
Drugs targeting DNA repair mechanisms inside cells are showing real promise for a range of tumors and AstraZeneca believes it ... Work on how cells repair damaged DNA landed Swedish, U.S. and Turkish scientists the Nobel Prize for Chemistry last year and ... Chief Executive Pascal Soriot said on Friday that while DNA damage response (DDR) was under-recognized by investors, ... Beyond immuno-oncology, AstraZeneca builds up DNA damage drugs. Published May 13, 2016. Reuters ...
He said that the publication had two main findings: humans evolved an inflammatory response when subjected to DNA damage, and ... Researchers offer the first evidence that DNA damage can lead to the regulation of inflammatory responses, the bodys reaction ... NIH Investigators Find Link Between DNA Damage And Immune Response. by Sam Savage ... Following damage, the TLRs interact with the tumor suppressor gene p53 to regulate the amount of inflammation. The NIEHS ...
... and functional aspects of DNA and RNA research. ... from track structure to DNA and chromosome damage," New Journal ... F. Ballarini, "Chromosome damage by ionizing radiation: a review," II Nuovo Cimento B, vol. 124, no. 4, pp. 443-458, 2009. View ... F. Ballarini, S. Bortolussi, A. M. Clerici, C. Ferrari, N. Protti, and S. Altieri, "From radiation-induced chromosome damage to ... M. N. Cornforth and J. S. Bedford, "A quantitative comparison of potentially lethal damage repair and the rejoining of ...
Findings from a recent study suggest that consumers who use e-cigarettes could be harming their DNA due to exposure to certain ... each biomarker was related to oxidative damage to DNA. This is cause for concern, as damage to DNA can worsen if consumers use ... Harmful metals in e-cigarettes could damage users DNA. Researchers say levels of zinc in these products pose serious health ... that are correlated to oxidative DNA damage," said researcher Prue Talbot. Harm to the body. To understand what effect these ...
... as well as a higher degree of the DNA damage such carboyls cause. ... Evidence of DNA-damaging compounds and DNA damage was collected ... four of the five e-cigarette users showed increased DNA damage related to acrolein exposure. The type of damage, a DNA adduct, ... vapers have higher levels of certain DNA-damaging compounds in their saliva. Worse, vapers sustain a kind of DNA damage that is ... occurs when toxic chemicals, such as acrolein, react with DNA. If the cell does not repair the damage so that normal DNA ...
  • Regulation of the DNA damage response is tightly connected to transcription and replication. (nih.gov)
  • However, unlike replication and transcription, DNA repair systems may be required anywhere, and at any time, whenever DNA damage occurs in the cell nucleus. (nih.gov)
  • B. Konze-Thomas, J. W. Levinson, V. M. Maher, and J. J. McCormick, Correlation among the rates of dimer excision, DNA repair replication, and recovery of human cells from potentially lethal damage induced by ultraviolet radiation, Biophys. (springer.com)
  • Polyomaviruses are a group of small DNA viruses, which have long been studied as a model for eukaryotic DNA replication. (springer.com)
  • Polyomaviruses manipulate host replication proteins, as well as proteins involved in DNA maintenance and repair, to serve as essential cofactors for productive infection. (springer.com)
  • 1994. T-antigen kinase inhibits simian virus 40 DNA replication by phospho-rylation of intact T antigen on serines 120 and 123. (springer.com)
  • Access to DNA packaged in nucleosomes is critical for gene regulation, DNA replication and DNA repair. (nature.com)
  • When lurking in the area during DNA replication, it bonds with adenine and causes the latter to pair with thymine rather than with its correct partner, unoxidized guanine. (scientificamerican.com)
  • Only a small fraction of cisplatin, however, actually interacts with DNA and the inhibition of DNA replication cannot solely account for its biological activity [ 5 ]. (hindawi.com)
  • In addition, recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, contributing to tolerance of DNA damage. (nature.com)
  • The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer etiology. (nature.com)
  • In addition to its role in preserving the genome, HR plays a prominent role in faithfully duplicating the genome by providing critical support for DNA replication and telomere maintenance. (nature.com)
  • Daily exposure to environmental agents (reactive oxygen species, methylating agents, UV light, and other ionizing radiation) and normal physiological processes (replication and recombination) all damage DNA. (qiagen.com)
  • If the cell does not repair the damage so that normal DNA replication can take place, cancer could result. (genengnews.com)
  • In turn, Chk1 regulates cyclin-dependent kinase 1 (CDK1) and CDK2, resulting in G 1 /S, S, and G 2 /M arrest to allow for DNA replication. (jci.org)
  • The Chen Laboratory studies many aspects of DNA damage response and DNA repair pathways, which include radiation-induced DNA damage response (DDR), BRCA1/2 and homologous recombination repair, replication stress pathway and lesion bypass, Fanconi anemia pathway and interstrand crosslink repair, Spartan/C1orf124/DVC1 and DNA-protein crosslink repair, and more recently the roles of DNA damage response in innate immunity. (mdanderson.org)
  • These chromatin responses "freeze" transcription and replication around the site of DNA lesion to facilitate subsequent repair. (frontiersin.org)
  • They also provide access to DDR sensors such as the Mre11-Rad50-Nbs1 (MRN) complex which binds double strand breaks (DSBs) and recruits ATM kinase (Figure 1 ) and the replication protein A (RPA) complex which responds predominantly to single strand DNA lesions and recruits ATR kinase. (frontiersin.org)
  • The binding of these kinases to damaged DNA triggers the recruitment of additional proteins, many of which become phosphorylated and activated to further transduce signals that orchestrate DNA replication, cell cycle control, transcription, repair of damage, and/or survival versus death. (frontiersin.org)
  • ATR normally recognizes single-strand breaks and other damage during DNA replication. (wikibooks.org)
  • One hypothesis stipulates that binding of mismatch repair (MMR) proteins to Me G/T mispairs arising during DNA replication triggers cell-cycle arrest and cell death. (genetics.org)
  • DNA replication and repair is an area where SKI excels. (mskcc.org)
  • DNA damage can occur at any time, but it's most likely to occur during DNA replication, which cells must do every time they divide. (mskcc.org)
  • DNA replication is inherently the time in a cell's life when most spontaneous chromosome breakages are happening," Dr. Petrini says. (mskcc.org)
  • Now, the authors of a study published in Cell Stem Cell last week (January 30) have connected that overgrowth with replication stress, subsequent DNA damage, and dysfunction in neural progenitor cells derived from induced pluripotent stem cells from patients with autism spectrum disorder. (the-scientist.com)
  • They also determined that when they treated the human cells with a drug that sped up their replication, the cells ended up with even more DNA damage. (the-scientist.com)
  • Next, the authors demonstrated that replication stress went hand-in-hand with an increase in double-strand DNA breaks in genes that have been shown to play a role in autism spectrum disorder. (the-scientist.com)
  • Together, the findings indicate that, in neural progenitor cells derived from people with autism, the overproliferation that causes macrocephaly leads to replication stress, which in turn causes DNA damage in genes associated with autism spectrum disorder and subsequently changes how the cells behave. (the-scientist.com)
  • We have now shown that, in the course of DNA replication prior to cell division, FaPy-G interacts with adenine, leading to the formation of FaPy-G:A base pairs . (phys.org)
  • This outcome is made possible by the fact that the cell's damage-control systems find it surprisingly difficult to distinguish the normal guanine base from its aberrant derivative FaPy-G during DNA replication . (phys.org)
  • Metabolic processes, UV exposure, DNA replication and merely packaging chromatin can introduce DNA damage at low rates. (fredhutch.org)
  • In a recent article published in Cell Cycle , Antonio Abeyta and colleagues show that NEK8 is a non-essential gene important for response to replication stresses including DNA damage. (fredhutch.org)
  • Importantly, researchers validated the screen results by showing that NEK8 contributes to repairing many types of DNA damage including: inter-strand crosslinks due to γ irradiation, mitomycin C mediated alkylation, and replication fork stalls by hydroxyurea. (fredhutch.org)
  • While these cells are viable, researchers found that they are hypersensitive to replication stresses including many DNA damaging agents as well as anti-mitotic compounds. (fredhutch.org)
  • To test if NEK8 protects DNA from MRE-11 activity, researchers treated NEK8-null MEFs with fluorescent dNTPs to be incorporated at sites of DNA synthesis and then stalled DNA replication using hydroxyurea. (fredhutch.org)
  • These stalled replication forks recruit DNA damage repair machinery and the fluorescent DNA is resected by MRE-11. (fredhutch.org)
  • Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. (sciencemag.org)
  • NFBD1 is not required for ssDNA generation at DNA damage sites and is not recruited by replication protein A (RPA)-coated ssDNA. (aacrjournals.org)
  • Our findings explain how UV-DDB detects occluded lesions in strongly positioned nucleosomes, and identify slide-assisted site exposure as a mechanism by which high-affinity DNA-binding proteins can access otherwise occluded sites in nucleosomal DNA. (nature.com)
  • A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key reactions that typify HR: homology search and DNA strand invasion. (nature.com)
  • As the researchers report in their paper in the November 29, 2007 online edition of Nano Letters (" DNA Damage Induced by Multi-walled Carbon Nanotubes in Mouse Embryonic Stem Cells "), the DNA damage induced by MWCNTs was indicated by Western blot analysis of 8-oxoguanine-DNA glycosylase 1 (OGG1) and by the induction of two key double-strand break repair proteins, Rad 51 and XRCC4. (medgadget.com)
  • Normal lymphocytes contain a number of restorative proteins, whose job it is to identify chromosomal damage and repair it or, if the damage is irreparable, prevent the cell from multiplying. (eurekalert.org)
  • Earlier research by André and Michel Nussenzweig, who is an investigator at HHMI, had identified other DNA repair proteins that are important during different phases of a B lymphocyte's life. (eurekalert.org)
  • In cell nucleus, DNA is wound around cores made of histone proteins. (businesswire.com)
  • One of the histone proteins, H2AX, plays important role in recognition of DNA damage. (businesswire.com)
  • New research performed on lab-grown human skin suggests that short but powerful bursts of THz radiation may both cause DNA damage and increase the production of proteins that help the body fight cancer. (businesswire.com)
  • At the same time, they observed THz-pulse induced increases in the levels of multiple tumor suppressor and cell-cycle regulatory proteins that facilitate DNA repair. (businesswire.com)
  • Acetylation of non-histone proteins is increasingly recognized as an important post-translational modification for controlling the actions of various cellular processes including DNA repair and damage response. (mdpi.com)
  • While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. (mdpi.com)
  • I think this is a hallmark paper because it shows an environmental effect that alters specific DNA sequences and the presumably the proteins that control their activity,' Hawley said. (news-medical.net)
  • Chromosomes are made of DNA that is tightly intertwined with proteins called histones to form chromatin. (redorbit.com)
  • However, researchers have discovered a new protein called TEX264 that can combine with other enzymes to find and destroy toxic proteins that bind to DNA and trigger damage. (upi.com)
  • By studying TEX264, scientists have gained new insight into how the body naturally finds harmful proteins and repairs the DNA damage they cause. (upi.com)
  • DNA damage response utilizes proteins involved in sensing, signaling, and repair of DNA damage. (frontiersin.org)
  • PARP inhibitors work, at least in part, by blocking the base excision DNA repair function of PARP proteins. (aacr.org)
  • After radiation exposure, damage-response proteins initiate DNA repair within minutes by localizing to sites of DNA double strand breaks (DSB). (wikibooks.org)
  • The UV-DDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. (rcsb.org)
  • Notably, DNA damage signaling proteins played a protective rather than sensitizing role in the MNNG response. (genetics.org)
  • For more than 20 years, Dr. Petrini has focused his attention on one biological machine in particular, an assembly of three large proteins called the Mre11 complex, which cells use to sense and repair DNA damage. (mskcc.org)
  • Working as a unit, these three proteins transmit a signal to another protein important for DNA repair called ATM. (mskcc.org)
  • ring finger protein 169 (RNF169) maintains the balance by limiting the deposition of DNA damage mediator proteins at the damaged chromatin. (sigmaaldrich.com)
  • H2AX is also responsible for recruiting response proteins to the site of DNA damage, and may play a role in DNA repair. (luminexcorp.com)
  • They found that cells in which the DNA damage pathway was triggered were the ones that exhibited an increase in the expression of special proteins on the cell surface. (scienceblog.com)
  • In the study, the authors suggest future research focus on improving the understanding of how these proteins contribute to DNA repair. (fiercebiotech.com)
  • FUS proteins containing ALS-linked mutations found sites of DNA damage, but then failed to bind HDAC1 and performed but a shoddy DNA repair. (alzforum.org)
  • However, the identification of proteins that become recruited to large chromatin domains flanking the DNA DBSs has made it possible to visualize these breaks indirectly by immunofluorescence ( 1 ). (sciencemag.org)
  • In cancers, evidence for the presence of DNA DSBs, such as phosphorylated histone H2AX and 53BP1 foci, was again present, but the DNA damage checkpoint pathway was compromised, most often by p53 mutations and less often by loss of expression of various checkpoint proteins, such as ATM, 53BP1, Chk2, or p53 ( 2 - 4 ). (sciencemag.org)
  • 2013. Viral interference with DNA repair by targeting of the single-stranded DNA binding protein rpa. (springer.com)
  • Binds to DDB1 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). (rcsb.org)
  • Loading of p53-binding protein 1 (53BP1) and receptor-associated protein 80 (RAP80) at DNA double-strand breaks (DSBs) drives cell cycle checkpoint activation but is counterproductive to high-fidelity DNA repair. (sigmaaldrich.com)
  • The intracellular localization of one such protein, p53 binding protein 1 (53BP1), was examined in cancer cell lines grown in tissue culture and revealed 53BP1 nuclear foci (about 10 to 20 per cell), whose presence is indicative of DNA DSBs. (sciencemag.org)
  • 2010. Multiple DNA damage signaling and repair pathways deregulated by Simian virus 40 large T antigen. (springer.com)
  • Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. (hindawi.com)
  • Cells respond to DNA damage by activating a complex network of the so-called checkpoint pathways to delay their cell-cycle progression and repair the defects. (nih.gov)
  • In this review we integrate findings on the emerging mechanisms of activation, the signalling pathways and the spatio-temporal organization of the intra-S-phase DNA-damage checkpoint and its impact on the cell-cycle machinery, and discuss its biological significance. (nih.gov)
  • Homologous recombination (HR) comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks (DSBs) and interstrand crosslinks (ICLs). (nature.com)
  • The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating cells by the direct or indirect induction of DNA lesions that are substrates for recombination pathways. (nature.com)
  • The ATM and ATR genes often initiate the DNA damage response, activating signal transduction pathways that arrest the cell cycle and increase the expression of DNA repair genes. (qiagen.com)
  • Incomplete DNA repair normally activates cell death pathways such as apoptosis. (qiagen.com)
  • The Human DNA Damage Signaling RT² Profiler PCR Array profiles the expression of 84 genes involved in DNA damage signaling pathways. (qiagen.com)
  • The Human DNA Repair EpiTect Methyl II Signature PCR Array profiles the promoter methylation status of a panel of 22 promoters of genes involved in DNA repair pathways such as base excision. (qiagen.com)
  • In particular, this review focuses on differential DNA damage response between stem cells and derived differentiated cells and the possible pathways that determine such differences. (bioone.org)
  • DNA repair pathways in tumours. (bioportfolio.com)
  • The DDR is a signaling network that includes cell cycle checkpoints and DNA repair and damage tolerance pathways. (intechopen.com)
  • DDR systems include DNA repair mechanisms, damage tolerance processes, and cell-cycle checkpoint pathways [ 3 ]. (intechopen.com)
  • The Chen Laboratory investigates the roles of tumor suppressor genes and oncogenes in DNA repair and other signaling pathways involved in tumor initiation, progression and metastasis. (mdanderson.org)
  • Relaxing this barrier allows two different DNA repair pathways greater access to the damage, preventing flawed DNA from being passed on as the cell divides, which causes genomic instability leading to cancer," said senior author Shiaw-Yih Lin, Ph.D., assistant professor in M. D. Anderson's Department of Systems Biology. (redorbit.com)
  • The team showed that normal BRIT1 aids repair of double-stranded DNA breaks by allowing access to two repair pathways: homologous recombination (HR) and non-homologous end-joining (NHEC). (redorbit.com)
  • Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. (mit.edu)
  • In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue. (mit.edu)
  • The term 'DNA damage response' (DDR) refers to a network of intracellular pathways that sense and resolve damaged DNA. (frontiersin.org)
  • Given the potentially devastating consequences of loss of DNA integrity, cells have evolved several interrelated pathways that they use to repair damaged DNA. (aacr.org)
  • Deficiencies in various DNA repair pathways are found in some patients with a number of types of cancer. (aacr.org)
  • Targeting DNA-repair pathways has promising therapeutic potential. (mskcc.org)
  • Although many signal transduction pathways promote MEF2 phosphorylation, thus modulating the prosurvival and neurogenic functions of MEF2 in the CNS, a signaling pathway that regulates MEF2-dependent survival in response to DNA damage has not yet been defined. (jneurosci.org)
  • This project fits in with the overall group aim to understand how DNA repair pathways function to prevent disease. (mendeley.com)
  • The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. (mdc-berlin.de)
  • The molecular pathways by which ATR functions in the mammalian DNA damage response pathway have not been studied as extensively as those involving ATM. (aacrjournals.org)
  • BRCA2 establishes a role of HR in cancer suppression, and also provides the nexus between HR and Fanconi anemia (FA), a classical DNA repair cancer predisposition syndrome that defines a molecular pathway with a function in ICL repair 12 , 13 . (nature.com)
  • Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification. (urotoday.com)
  • DNA mismatch repair is an important pathway of mutation avoidance. (nih.gov)
  • QIAGEN provides a broad range of assay technologies for DNA damage and repair research that enables analysis of gene expression and regulation, epigenetic modification, genotyping, and signal transduction pathway activation. (qiagen.com)
  • Pioneering work from the Dong laboratory previously demonstrated that the DDR is activated in cisplatin and ischemia-induced AKI ( 3 - 5 ), highlighting the pathway as a therapeutic target to protect against kidney damage. (jci.org)
  • In this issue, Kishi and colleagues ( 6 ) hypothesized that the DDR plays a critical role in renal proximal tubule (PT) cells, such that loss of the pathway would impair adaptive cellular DNA repair and hasten fibrotic changes. (jci.org)
  • Normally CHK2 is involved in the signal response pathway that begins when DNA is damaged and results in a temporary stoppage of cell division until the damage is fixed. (rxpgnews.com)
  • Data are presented for patients with and without pathogenic germline or somatic mutations in HR DNA repair pathway genes (i.e. (jci.org)
  • However, mutations in these and other DNA repair pathway genes can also arise during a patient's lifetime and are found in sporadic tumors. (aacr.org)
  • Our current understanding of genetic deficiencies in DNA repair pathway genes is already being exploited therapeutically . (aacr.org)
  • Cancer cells that have deficiencies in the homologous recombination DNA repair pathway, for example, ovarian cancer cells with certain BRCA1 or BRCA 2 mutations, are particularly susceptible to having their base excision DNA repair pathway blocked by a PARP inhibitor. (aacr.org)
  • It has also been shown to be promising as a treatment for men with prostate cancer harboring DNA repair-pathway deficiencies. (aacr.org)
  • However, the only type of stress that set off the sequence of events associated with impairment of a cell's genetic material - the DNA damage pathway - was exposure to radiation and chemotherapy drugs. (scienceblog.com)
  • Prior studies have shown that the DNA damage pathway is activated in precancerous lesions, as well as many advanced tumors. (scienceblog.com)
  • We don't have direct information about the role of the DNA damage pathway in regulating immune responses to infectious diseases, but given what we have shown here, it is certainly plausible that it contributes to the expression of the NKG2D ligand," said Raulet. (scienceblog.com)
  • FUS is an integral part of the DNA damage response pathway," concluded Tsai. (alzforum.org)
  • Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. (sciencemag.org)
  • RNAi-based gene silencing of 53BP1 or NFBD1 has shown impaired phosphorylation of SQ/TQ [ataxia-telangiectasia mutated/ATM and Rad3-related (ATM/ATR) substrates] at IRIF, intra-S, and G 2 -M checkpoints and has thereby revealed essential roles for 53BP1 and NFBD1 in the DNA damage signaling pathway. (aacrjournals.org)
  • it associates with IR-induced foci and functions upstream of BRCA1 in the DNA damage response pathway (10) . (aacrjournals.org)
  • Currently, quantitative live cell imaging techniques combined with methods to induce local DNA damage in a small region of the nucleus are contributing substantially to unravelling the molecular mechanisms underlying the cellular response to DNA damage. (nih.gov)
  • Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. (nature.com)
  • Cellular DNA damage was validated using lymphocyte cell cultures. (ilo.org)
  • Ultraviolet light, environmental chemicals, even the by-products of normal cellular metabolism all conspire to continually assault the DNA of humans and every other living thing. (scientificamerican.com)
  • And that means Nakabeppu and his colleagues may have shown how environmental damage leads to cellular mutation, for good and for ill. (scientificamerican.com)
  • The clinically acquired resistance can be caused by decreased drug accumulation which includes reduced uptake or increased efflux of cisplatin, increased drug detoxification by cellular thiols, increased DNA repair or tolerance of cisplatin-damaged DNA and the ability of the cancer cells to evade cisplatin-induced cell death. (hindawi.com)
  • In this paper, we primarily focused on recent studies on cellular responses to cisplatin-induced DNA damage although we briefly discussed steps leading to cisplatin-induced DNA damage. (hindawi.com)
  • A popular theory postulates that aging is triggered by cellular accumulation of oxidative damage. (sciencemag.org)
  • Mice doubly mutant for XPD and a second gene required for nucleotide-excision repair, XPA, showed greatly accelerated aging that correlated with an increased cellular sensitivity to oxidative DNA damage. (sciencemag.org)
  • Particularly damaging to our cellular DNA are the particles from the underground system in Stockholm, Sweden, according to a new doctoral thesis from Karolinska Institutet. (innovations-report.com)
  • The results, which are presented in her thesis Particularly harmful particles show that particles from the Stockholm underground are much more damaging to cellular DNA than the other sources tested (e.g. wood smoke and cars). (innovations-report.com)
  • Cells unable to sense and repair DNA damage may continue to grow and divide, eventually causing cellular dysfunction and death, a hallmark of diseases such as neurological defects and infertility. (qiagen.com)
  • Cellular DNA damage can be caused by exogenous insults, such as drugs and UV light, or endogenous stressors such as ROS. (jci.org)
  • Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed as the DNA damage response (DDR). (intechopen.com)
  • DNA damage exists in all cellular organisms, and DNA, the genetic material in each living cell is the fundamental unit of life and its integrity and stability are essential to life [ 1 ]. (intechopen.com)
  • They then studied the sample for the presence of phosphorylated H2AX, which "flags" the DNA double strand break site and attracts cellular DNA repair machinery to it. (businesswire.com)
  • Researchers say they have found the 'first direct biological evidence' of damage in veterans with Gulf War illness to DNA within cellular structures that produce energy in the body. (news-medical.net)
  • Like a mechanic popping the hood of a car to get at a faulty engine, a tumor-suppressing protein allows cellular repair mechanisms to pounce on damaged DNA by overcoming a barrier to DNA access. (redorbit.com)
  • RxPG] Dartmouth Medical School geneticists have discovered that DNA damage resets the cellular circadian clock, suggesting links among circadian timing, the cycle of cell division, and the propensity for cancer. (rxpgnews.com)
  • Aging occurs at the level of individual cells, a complex interplay between intrinsic 'programming' and exogenous 'wear and tear', with genetically-determined cellular capacity to repair environmentally-induced DNA damage playing a central role in the rate of aging and its specific manifestations. (elsevier.com)
  • Autophagy and the DNA damage response (DDR) are biological processes essential for cellular and organismal homeostasis. (frontiersin.org)
  • The damage caused by oxidative stress is linked to cellular and genetic mutations which cause the development of tumors. (greenprophet.com)
  • Therefore, the discovery of how ATM is activated could help guide the development of ways to improve cellular responses to DNA damage, including responses to oxidative stress that are either induced or natural. (innovations-report.com)
  • SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks, G0/G1 cell-cycle arrest, and cellular senescence. (jci.org)
  • Then they showed that this DNA damage led to problems with migration and cellular connections. (the-scientist.com)
  • Phys.org) -Adventitious changes in cellular DNA can endanger the whole organism, as they may lead to life-threatening illnesses like cancer. (phys.org)
  • For example, cellular respiration , i.e. the reduction of inspired oxygen to water, which powers cell function, also generates highly reactive oxygen species that can damage DNA, with the purine bases G and A being particularly susceptible to this kind of attack. (phys.org)
  • Cellular response to DNA damage is critical to maintain genomic stability. (aacrjournals.org)
  • however, it remains unknown how these lesions are recognized in chromatin, in which nucleosomes restrict access to DNA. (nature.com)
  • Fig. 5: Principles that govern DNA damage recognition in chromatin. (nature.com)
  • Rodriguez, Y., Hinz, J. M. & Smerdon, M. J. Accessing DNA damage in chromatin: Preparing the chromatin landscape for base excision repair. (nature.com)
  • ATP-dependent chromatin remodeling is a fundamental mechanism used by cells to relax chromatin in DNA repair, but the detailed molecular mechanism by which it is recruited to DNA lesions in response to damage signaling has been largely unknown. (redorbit.com)
  • Our studies demonstrate a novel mechanism by which BRIT1 recruits chromatin remodeling factors to DNA lesions to facilitate chromatin relaxation and DNA repair," Peng said. (redorbit.com)
  • Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. (mit.edu)
  • Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. (mit.edu)
  • We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. (mit.edu)
  • Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. (mit.edu)
  • These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage. (mit.edu)
  • In contrast, homologous recombination (HR), postreplicative repair, DNA helicases, and chromatin maintenance factors protect yeast cells against the cytotoxicity of this chemical. (genetics.org)
  • Dai explains that, in response to DNA damage, eukaryotic cells, including ES cells, have developed several mechanisms to protect genomic integrity. (medgadget.com)
  • LONDON - Drugs targeting DNA repair mechanisms inside cells are showing real promise for a range of tumors and AstraZeneca believes it is well ahead of rivals in the emerging cancer field. (foxnews.com)
  • F. Ballarini, S. Bortolussi, A. M. Clerici, C. Ferrari, N. Protti, and S. Altieri, "From radiation-induced chromosome damage to cell death: modelling basic mechanisms and applications to Boron neutron capture therapy," submitted to Radiation Protection Dosimetry . (hindawi.com)
  • While these investigations of the biological effects of intense THz pulses are only just beginning," said Lyubov Titova, with the University of Alberta and a member of the research team, "the fact that intense THz pulses can induce DNA damage but also DNA repair mechanisms in human skin tissue suggests that intense THz pulses need to be evaluated for possible therapeutic applications. (businesswire.com)
  • Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. (mdpi.com)
  • University of Oregon biologists have used the model organism Caenorhabditis elegans to identify molecular mechanisms that produce DNA damage in sperm and contribute to male infertility following exposure to heat. (news-medical.net)
  • The underlying mechanisms that damage sperm and impair fertilization are not completely understood. (news-medical.net)
  • The data presented in this paper suggest that another way egg and sperm develop differently is in how tightly they control the ability of mobile DNA elements, which are also known as 'jumping genes' or transposons, to move in the genome, and how sensitive to heat stress those mechanisms are in preventing that movement. (news-medical.net)
  • Researchers revealed how nucleotides damaged by oxidative stress become inserted into DNA strands and block DNA repair mechanisms. (nih.gov)
  • "But it's important to remember that alcohol clearance and DNA repair systems are not perfect and alcohol can still cause cancer in different ways, even in people whose defense mechanisms are intact," he concluded. (rt.com)
  • However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. (mit.edu)
  • This book is an excellent single source of information for anyone interested in DNA repair, mechanisms of aging, or certainly their intersection. (elsevier.com)
  • Almonds and Brussels sprouts, likewise, may protect against DNA damage by boosting our own DNA repair mechanisms. (nutritionfacts.org)
  • Uncovering the mechanisms by which autophagy and DDR are intertwined provides novel insight into the pathobiology of conditions associated with accumulation of DNA damage, including cancer and aging, and novel concepts for the development of improved therapeutic strategies against these pathologies. (frontiersin.org)
  • Our technique for identifying activated ATM is so sensitive that we ve been able to show that it takes only a couple of breaks in the entire DNA of the cell to activate and initiate all of the cell s response mechanisms," Kastan said. (innovations-report.com)
  • The identification of these molecular mechanisms and the development of specific antibodies against activated ATM might also provide a very sensitive way to determine if cells in a person have been exposed to an agent or toxin that damages DNA, according to Kastan. (innovations-report.com)
  • The Royal Swedish Academy of Sciences said work by the three scientists on DNA repair had provided "fundamental knowledge" about how cells function and shed light on the mechanisms behind both cancer and aging. (seattletimes.com)
  • We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. (hindawi.com)
  • Enhanced expression of p53 may also trigger cell death by apoptosis if the DNA damage is beyond repair, while under normal conditions (absence of DNA damage) p53 is expressed at low levels" he says. (medgadget.com)
  • demonstrate that following kidney epithelial cell injury, DNA repair, rather than cell proliferation, plays the central role in recovery and longevity by minimizing apoptosis, G 2 /M cell-cycle arrest, and subsequent fibrosis. (jci.org)
  • Commitment signalling for apoptosis, or DNA repair and its relevance to aging and age-dependent diseases (E. Wang, R. Marcotte, H.T. Papaconstantinou, J. Papaconstantinou). (elsevier.com)
  • As a result of this chain of command, the damage will either be repaired, or the cell will be put out of its misery through a natural culling process called apoptosis. (mskcc.org)
  • This kit is a sensitive and valuable tool for studying factors that induce DNA damage and affect DNA repair, allowing exploration of the linkage between DNA damage, cell cycle checkpoints, and initiation of apoptosis. (luminexcorp.com)
  • If the damage is too severe for the cell to repair on its own, it can trigger cell death, a process known as apoptosis. (scienceblog.com)
  • Chk2 −/− thymocytes were resistant to DNA damage-induced apoptosis. (sciencemag.org)
  • In addition, in precancerous lesions, these DNA DSBs activate p53 , which, by inducing apoptosis or senescence, raises a barrier to tumor progression. (sciencemag.org)
  • Further, in the panel of cancer cell lines examined, those cell lines with the highest number of 53BP1 foci per cell had p53 mutations, possibly reflecting a selection for p53 inactivation, because p53 induces apoptosis or senescence in response to DNA DSBs ( 1 , 2 ). (sciencemag.org)
  • Without such response and repair, the cell will eventually undergo apoptosis or pass on its altered DNA to daughter cells. (aacrjournals.org)
  • Now Japanese researchers have shown how environmentally damaged letters lead to transcription flaws and, ultimately, human diversity. (scientificamerican.com)
  • By fluorescently labeling monoclonal antibodies that attach to DNA sites where 8-oxoG has made its changes the researchers revealed that the oxidized guanine does not occur randomly throughout the chromosome but rather clusters in certain areas. (scientificamerican.com)
  • The researchers gave ethanol to mice and then used chromosome analysis and DNA sequencing to study genetic damage on the body by acetaldehyde, produced during the metabolic processing of alcohol. (mercola.com)
  • 9 The researchers chose to study blood stem cells since they quickly replicate and readily spread genetic damage throughout the body. (mercola.com)
  • The researchers found acetaldehyde breaks and damages DNA in blood cell stem cells, leading to rearranged chromosomes and permanently altering DNA sequences. (mercola.com)
  • Researchers offer the first evidence that DNA damage can lead to the regulation of inflammatory responses, the body's reaction to injury. (redorbit.com)
  • Now, the researchers are taking advantage of another NIEHS translational program, the Environmental Polymorphisms Registry (EPR) ( http://www.niehs.nih.gov/research/clinical/join/epr/index.cfm ), an ongoing study to collect DNA samples from nearly 20,000 North Carolinians. (redorbit.com)
  • The researchers are most concerned about the levels of zinc, as exposure to the metal in these quantities can lead to several health concerns, including damage to consumers' DNA. (consumeraffairs.com)
  • Since the ATM protein is mutated in a number of lymphomas -- cancers of the lymph and immune system -- the new finding suggests to researchers that the lymphocytes could have been living with DNA damage for a long time, and that this damage likely plays a role in later chromosomal translocations, rearrangements of genetic materials that can lead to cancer. (eurekalert.org)
  • In a study published late last year , researchers Rachel Miller and Martin Wiedmann, both of whom work in Cornell's Department of Food Science, looked at five different salmonella strains known to produce a toxin that can cause cell damage. (foodandwine.com)
  • This schematic shows what the researchers suspect is happening to DNA molecules when exposed to strong pulses of THz radiation. (businesswire.com)
  • According to the researchers, this raised the question: "Can intense THz pulses destabilize DNA structure enough to cause DNA strand breaks? (businesswire.com)
  • In a first of its kind study, the Canadian researchers exposed laboratory-grown human skin tissue to intense pulses of THz electromagnetic radiation and have detected the telltale signs of DNA damage through a chemical marker known as phosphorylated H2AX. (businesswire.com)
  • Washington, April 01(ANI): Researchers at the National Institute of Environmental Health Sciences have offered the first evidence that DNA damage can lead to the regulation of inflammatory responses, the body's reaction to injury. (thaindian.com)
  • In the latter, the researchers saw higher amounts of DNA damage in sperm, but not eggs. (news-medical.net)
  • In blood tests, researchers observed more lesions and more mitochondrial DNA--that is, extra copies of genes--in veterans with Gulf War illness, relative to controls without the illness, suggesting excess DNA damage. (news-medical.net)
  • Greater mtDNA damage is consistent with mitochondrial dysfunction, which may contribute to symptoms of GWI, as well as persistence of this illness over time,' the researchers write. (news-medical.net)
  • Falvo explains that the researchers used a new technique developed in the lab of his team's collaborator that allowed them to evaluate the quality of the mitochondrial DNA directly from total DNA without having to isolate the mitochondria. (news-medical.net)
  • The levels of nuclear DNA damage were also elevated in the veterans with GWI, but did not reach 'statistical significance,' the researchers say. (news-medical.net)
  • Researchers highlighted the importance of understanding the DNA blueprint within stem cells citing one simple reason: when healthy stem cells are corrupted, they can give rise to cancer. (rt.com)
  • The researchers found that the resetting effect of DNA damage requires the period-4 clock protein, and that period-4 is the homolog, the Neurospora version, of the mammalian checkpoint kinase. (rxpgnews.com)
  • With the understanding that eating plants protects our DNA, and eating animals may damage it, as I talked about in previous reviews, this year Slovakian researchers measured the total number of DNA breaks in vegetarians compared to meat-eaters, led by a Dr. Krajcovicová-Kudlácková-Dr. K! (nutritionfacts.org)
  • The researchers then tested the extracts' ability to protect DNA strands against damage by hydroxide radicals. (naturalnews.com)
  • The St. Jude researchers found that ATM is activated by a signal from damaged DNA only seconds after the damage occurs. (innovations-report.com)
  • The St. Jude researchers also developed an antibody that specifically recognizes activated ATM, and thus identifies only those ATM molecules that are responding to DNA damage. (innovations-report.com)
  • University of Leicester researchers writing in the journal Chemical Research in Toxicology say they have found "convincing evidence" that cannabis smoke damages DNA and it could potentially increase the risk of cancer development in humans. (science20.com)
  • The researchers add that the ability of cannabis smoke to damage DNA has significant human health implications especially as users tend to inhale more deeply than cigarette smokers, which increases respiratory burden. (science20.com)
  • These results provide evidence for the DNA damaging potential of cannabis smoke," the researchers conclude, "implying that the consumption of cannabis cigarettes may be detrimental to human health with the possibility to initiate cancer development. (science20.com)
  • Later this week, more than 200 researchers will convene in Montreal for a four-day conference on DNA Repair: Tumor Development and Therapeutic Response organized by the American Association for Cancer Research (AACR). (aacr.org)
  • A comprehensive understanding of both Histone H2A.X activity and the consequence of its activation can provide researchers with useful information in characterizing the DNA damage response. (luminexcorp.com)
  • Researchers in the Vetsuisse Faculty have now decoded the mechanism that repairs DNA damaged in this way. (medicalxpress.com)
  • Researchers in the Taniguchi Lab (Human Biology Division) recently expanded this understanding by identifying a protein kinase (NEK8) previously unknown to regulate DNA damage response. (fredhutch.org)
  • DNA damage repair signaling is known to be mediated by multiple kinases thus researchers performed an RNAi screen to identify any kinases not previously known to regulate this process. (fredhutch.org)
  • The protein alpha-synuclein helps repair DNA breaks in brain cells, researchers discovered. (fiercebiotech.com)
  • What's more, they could see that when the protein formed Lewy bodies, there was an increase in double-strand DNA breaks in both mice and human tissue, the researchers reported. (fiercebiotech.com)
  • A new study published by University of Leicester researchers has found 'convincing evidence' that cannabis smoke damages DNA in ways that could potentially increase the risk of cancer development in humans. (opposingviews.com)
  • This review will focus on polyomaviruses and their interaction with ATM- and ATR-mediated DNA damage responses and the effect of this interaction on host genomic stability. (springer.com)
  • A network comparison of genetic interactions mapped at two conditions reveals genetic responses to DNA damage in yeast. (sciencemag.org)
  • They collected urine samples from all of the participants and evaluated their DNA responses. (consumeraffairs.com)
  • To determine whether ex vivo responses to IR might lead to a useful clinical test, we hypothesized that cells from patients with radiation toxicity have abnormal transcriptional responses to DNA damage. (pnas.org)
  • In 12 chapters, 'The Role of DNA Damage and Repair in Cell Aging' provides an intellectual framework for aging of mitotic and post-mitotic cells, describes a variety of model systems for further studies, and reviews current concepts of DNA responses and their relationship to the phenomenon of aging. (elsevier.com)
  • Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. (jci.org)
  • Dual-utility NLS drives RNF169-dependent DNA damage responses. (sigmaaldrich.com)
  • Jeon GS, Kim KY, Hwang YJ, Jung MK, An S, Ouchi M, Ouchi T, Kowall N, Lee J, Ryu H . Deregulation of BRCA1 Leads to Impaired Spatiotemporal Dynamics of γ-H2AX and DNA Damage Responses in Huntington's Disease . (alzforum.org)
  • These novel findings help clarify where NFBD1 functions in DNA damage early responses. (aacrjournals.org)
  • We find that UV-DDB binds UV-damaged nucleosomes at lesions located in the solvent-facing minor groove without affecting the overall nucleosome architecture. (nature.com)
  • A sensitive and complex DNA damage response (DDR) has evolved to detect these lesions, delay cell-cycle progression, and repair the damage. (jci.org)
  • We highlight published data suggesting that autophagy is activated by DNA damage and is required for several functional outcomes of DDR signaling, including repair of DNA lesions, senescence, cell death, and cytokine secretion. (frontiersin.org)
  • 100,000 DNA lesions per day. (wikibooks.org)
  • A hairpin between blades 5 and 6 inserts into DNA minor groove and mediates recognition of lesions and separation of the damaged and undamaged strands. (rcsb.org)
  • In the precancerous lesions, before p53 mutations were acquired, 53BP1 localized at foci and histone H2AX, ataxia telangiectasia (ATM), Chk2, and p53 were phosphorylated, suggesting the presence of DNA DSBs ( 3 , 4 ). (sciencemag.org)
  • TUESDAY, June 27, 2017 (HealthDay News) -- When people work the night shift, their bodies might have less capacity to repair everyday damage to cells' DNA, a small study hints. (medicinenet.com)
  • Nevertheless, there are arguments against this point of view (1) and, even if damage to DNA is the important element in cancer initiation, one should always keep in mind the possibilities that the switch from normal to cancer cells may arise from faulty transcription and hence translation (as seems to be the case in the death of UV-irradiated arrested human fibroblasts). (springer.com)
  • V. M. Maher, D. J. Dorney, A. L. Mendrala, B. Konze-Thomas, and J. J. McCormick, DNA excision-repair processes in human cells can eliminate the cytotoxic and mutagenic consequences of ultraviolet irradiation, Mutat. (springer.com)
  • In response to any source of DNA damage, cells must initiate an effective DNA damage response (DDR) to maintain genomic integrity, wherein two protein kinases, ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), are major regulators of DNA damage recognition and repair. (springer.com)
  • 2012. Defective DNA repair and cell cycle arrest in cells expressing merkel cell polyomavirus T antigen. (springer.com)
  • Subtle changes in the pairing of the chemical letters of DNA--adenine, cytosine, guanine and thymine--produce new cells with different traits than their ancestors. (scientificamerican.com)
  • It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. (hindawi.com)
  • How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. (hindawi.com)
  • Following DNA damage, cells may either repair the damage and start progressing through the cell cycle or if they cannot repair the damage, cells proceed to die [ 5 ]. (hindawi.com)
  • LONDON (Reuters) - Scientists studying the effects of the potentially game-changing gene editing tool CRISPR/Cas9 have found it can cause unexpected genetic damage which could lead to dangerous changes in some cells. (reuters.com)
  • CRISPR/Cas9, one of the newest genome editing tools, can alter sections of DNA in cells by cutting at specific points and introducing changes at that location and is seen by many as a promising way to create treatments for diseases such as HIV or cancer. (reuters.com)
  • Bradley's team carried out a full systematic study in both mouse and human cells and discovered that CRISPR/Cas9 frequently caused extensive mutations including large genetic rearrangements such as DNA deletions and insertions. (reuters.com)
  • Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid. (urotoday.com)
  • It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatch repair are resistant, or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. (nih.gov)
  • The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6-methylguanine and 6-thioguanine in DNA. (nih.gov)
  • 11 "We saw huge amounts of DNA damage in these cells. (mercola.com)
  • Some cancers develop due to DNA damage in stem cells. (mercola.com)
  • The damage is caused when these particles enter the body and form free radicals in the body's cells. (innovations-report.com)
  • Cells must repair DNA damage to prevent mutations from propagating and accumulating, and to maintain genome integrity and stability. (qiagen.com)
  • Work on how cells repair damaged DNA landed Swedish, U.S. and Turkish scientists the Nobel Prize for Chemistry last year and AstraZeneca's recently approved Lynparza is an early example of a drug that builds on this new understanding. (foxnews.com)
  • Likewise, DNA from oral cells were isolated, hydrolyzed to nucleosides, and analyzed by both targeted and nontargeted DNA adductomics approaches. (genengnews.com)
  • Although a great deal of knowledge has been generated, a debate over the importance of repairing damaged cells versus replacing them by proliferation remains. (jci.org)
  • When a strand of DNA breaks in the body's cells, it normally does not take long until it has been repaired. (eurekalert.org)
  • Another large research question is how cells repair damaged DNA and consequently prevent cancer, for example. (eurekalert.org)
  • A protein long known to be involved in protecting cells from genetic damage has been found to play an even more important role in protecting the cell's offspring. (eurekalert.org)
  • New research by a team of scientists at Rockefeller University, Howard Hughes Medical Institute and the National Cancer Institute shows that the protein, known as ATM, is not only vital for helping repair double-stranded breaks in DNA of immune cells, but is also part of a system that prevents genetic damage from being passed on when the cells divide. (eurekalert.org)
  • Early in the life of B lymphocytes -- the immune cells responsible for hunting down foreign invaders and labeling them for destruction -- they rearrange their DNA to create various surface receptors that can accurately identify different intruders, a process called V(D)J recombination. (eurekalert.org)
  • The ATM protein appears to have two roles in a B cell: It helps repair the DNA double-strand breaks, and it activates the cell-cycle checkpoint that prevents genetically damaged cells from dividing. (eurekalert.org)
  • According to the Cornell Chronicle , when unleashed upon human cells grown in the lab, these strains were "found to lead to hallmark signatures that indicate the presence of DNA damage" - an effect that could impact those struck with the illness later in life. (foodandwine.com)
  • The more you expose your body's cells to DNA damage, the more DNA damage that needs to be repaired, and there may one day be a chance that the DNA damage is not correctly repaired. (foodandwine.com)
  • To maintain genomic stability and avoid transmission of mutations into progenitors cells, stem cells have robust DNA damage response signaling, a contrast to somatic cells. (bioone.org)
  • Kalpana Mujoo , E. Brian Butler , Raj K. Pandita , Clayton R. Hunt , and Tej K. Pandita "Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations," Radiation Research 186(1), 17-26, (22 June 2016). (bioone.org)
  • 8 By understanding and identifying these dependencies, we can use precision medicine approaches and targeted DDR inhibitors to maximise DNA damage and selectively kill cancer cells. (astrazeneca.com)
  • Tens of thousands of DNA damage events take place in human cells every day. (astrazeneca.com)
  • 5,6 To repair these DNA damage events and enable cells to function normally, a series of processes takes place, collectively known as the DNA Damage Response (DDR). (astrazeneca.com)
  • In response to the DNA damage, cells rapidly recruit a sophisticated network which is called DNA damage-response (DDR) systems. (intechopen.com)
  • THz photons, like their longer wavelength cousins in the microwave range, are not energetic enough to break the chemical bonds that bind DNA together in the nucleus of cells. (businesswire.com)
  • The excited state lifetime of compounds used in sunscreens such as menthyl anthranilate, avobenzone or padimate O is 1,000 to 1,000,000 times longer than that of melanin, and therefore they may cause damage to living cells that come in contact with them. (wikipedia.org)
  • Large numbers of the resulting DNA nicks can be lethal to cells and serve as a jumping off point for the development of disease. (nih.gov)
  • DNA repair efficiency dropped by between 40 and 60 percent in cells with BRIT1 knocked down that were then exposed to ionizing radiation, allowing many damaged cells to divide and pass on their genetic defects. (redorbit.com)
  • Alcohol causes irreparable damage in the DNA of stem cells, enhancing the risk of developing cancer, and costing some hard drinkers "more than just a hangover," British scientists say. (rt.com)
  • Scientists discovered that acetaldehyde can break and damage DNA within blood stem cells, causing rearranged chromosomes as well as permanently altering the DNA sequences within these cells. (rt.com)
  • In the British scientists' study, when mice lacking the critical ALDH enzyme (ALDH2) were given alcohol, it resulted in four times as much DNA damage in their cells compared with mice with the fully-functioning enzyme. (rt.com)
  • Cells also have a second line of defense in a variety of DNA repair systems. (rt.com)
  • Although most of the time they reverse different types of DNA damage, some people carry mutations so their cells aren't capable of carrying out any such 'repair work. (rt.com)
  • We hope that by understanding how our cells fix DNA breaks, we can help meet some of these challenges, as well as explore new ways of treating cancer in the future. (upi.com)
  • In 2006, the World Health Organization (WHO) concluded, after a thorough review of recent research on stevia and its related compounds, that stevia does not damage the genes of humans or other animals, and that many of the toxic effects seen in laboratory studies do not occur in living cells. (naturalnews.com)
  • Scientists at St. Jude Children s Research Hospital have discovered a novel biochemical process that plays a critical role in helping cells in the body respond to DNA damage, such as that caused by exposure to radiation, environmental toxins or free radicals. (innovations-report.com)
  • The new St. Jude findings thus provide new insights into the way cells signal to both Brca1 and p53 following DNA damage. (innovations-report.com)
  • Since damage to the DNA appears to contribute to the vast majority of human cancers, enhancing the response of cells to DNA damage could reduce cancer development, Kastan noted. (innovations-report.com)
  • A byproduct of alcohol consumption causes mutations in the DNA of mouse blood stem cells, and some of the breaks are not repaired. (the-scientist.com)
  • WIKIMEDIA, TIIA MONTO A metabolite of alcohol known as acetaldehyde, which occurs naturally at low levels, causes double-stranded breaks in the DNA of mouse blood stem cells, according to a study published today (January 3) in Nature . (the-scientist.com)
  • This paper provides very strong evidence that an alcohol metabolite causes DNA damage [including] to the all-important stem cells that go on to make tissues. (the-scientist.com)
  • This thought-provoking research highlights the damage alcohol can do to our cells, costing some people more than just a hangover," Linda Bauld of Cancer Research UK says in a press release . (the-scientist.com)
  • Genomic deletions promote cancer by carving up or eliminating tumor-suppressor genes, but now scientists report in the journal Nature that the collateral damage they inflict on neighboring genes exposes cancer cells to vulnerabilities and new avenues for attack. (mdanderson.org)
  • Cells have molecules that directly sense damaged DNA and repair it. (mskcc.org)
  • He also showed that this complex binds to damaged DNA in human cells, a critical step in demonstrating that the complex is a sensor of DNA damage. (mskcc.org)
  • Cancer cells often depend on activated Chk1, a central cell cycle checkpoint regulator in the DDR network, as a strategy to survive and replicate despite accumulating extensive DNA damage due to replicative stress or in response to chemotherapeutic intervention. (prnewswire.com)
  • It works by exploiting DNA Damage Response defects which are specific to cancer cells, and kills them whilst sparing normal cells. (astrazeneca.com)
  • Every day, DNA in our cells is damaged thousands of times by natural causes and external factors. (astrazeneca.com)
  • 1 The body has developed systems to protect the cells from DNA damage, called the DNA Damage Response or DDR. (astrazeneca.com)
  • 2 Cancer cells with a DNA Damage Response deficiency are heavily reliant on remaining 'back up' DNA Damage Response systems. (astrazeneca.com)
  • DNA Damage Response Inhibition exploits these defects by blocking the remaining response systems cancer cells are relying on to survive, which in turn causes them to die. (astrazeneca.com)
  • ABOVE: Neural progenitor cells derived from individuals with autism spectrum disorder (right) exhibit increased DNA damage (indicated as red dots on DNA labeled in blue) compared to those derived from typical individuals (left). (the-scientist.com)
  • In 2016 , a group led by Schwer and Frederick Alt of Boston Children's Hospital showed that mice have clusters of double-strand DNA breaks in the genomes of their neural progenitor cells. (the-scientist.com)
  • Rusty Gage , a neuroscientist at the Salk institute, Meiyan Wang , a graduate student in the Gage lab, and their colleagues collaborated with Alt to explore whether or not these same damaged clusters would show up in the genomes of human neural progenitor cells. (the-scientist.com)
  • Because the research team had shown before that the cells from people with autism overproliferate even without drug treatment, they hypothesized that those cells would also have more double-strand DNA breaks. (the-scientist.com)
  • That was indeed the case, and they discovered that the cells also spent less time in S-phase, the portion of the cell cycle during which cells replicate their DNA. (the-scientist.com)
  • Wang acknowledges that it's still not known if this DNA damage leads to increased mutations in these cells and, by extension, if there are increased somatic mutations in patients with macrocephalic autism. (the-scientist.com)
  • In order to validate that the level of H2A.X activation is accurate, a total H2A.X antibody is multiplexed by flow cytometry to allow for normalization of the total and phospho H2A.X levels, since DNA content levels vary based on which stage cells are within the cell cycle. (luminexcorp.com)
  • The Histone H2A.X DNA Damage Dual Detection Kit is designed to allow the researcher to monitor and accurately measure phospho-specific Histone H2A.X activation in a population of cells. (luminexcorp.com)
  • Interestingly, substitution of endogenous MEF2D with an shRNA-resistant phosphomimetic MEF2D mutant protects cerebellar granule cells from cell death after DNA damage, whereas an shRNA-resistant nonphosphorylatable MEF2D mutant does not. (jneurosci.org)
  • DNA sustains damage in multiple ways, such as when it is copied as cells divide or in response to chemicals or ultraviolet rays from the sun. (seattletimes.com)
  • Working at Yale University, Sancar mapped the mechanism that cells use to repair UV-damaged DNA. (seattletimes.com)
  • Some research into developing new cancer drugs is based on the idea of sabotaging the DNA repair that keeps cancer cells alive. (seattletimes.com)
  • These "ligands" on the membrane are specific to the NKG2D receptor on natural killer cells and are used to flag damaged cells for destruction. (scienceblog.com)
  • What's new about our study is that we found that cells with damaged DNA can also involve other cells in the fight, triggering a mechanism that signals other cells - specifically NK cells - to attack. (scienceblog.com)
  • Pacheco and her colleagues looked at how two different types of nanoparticles could cause DNA damage in the MCF-7 line of breast cancer cells. (phys.org)
  • We observed both dose-dependent and time-dependent increases in DNA damage in breast cancer cells exposed to either aqueous colloidal silica or C60 fullerenes," Pacheco said. (phys.org)
  • The DNA in our cells controls the form and function of every cell type in our bodies. (phys.org)
  • Further insights into the reasons why FaPy-G often eludes the cell's detection and correction systems could help to improve the treatment of cancer, as the inhibition of DNA repair processes in tumor cells increases their sensitivity to chemotherapeutic drugs. (phys.org)
  • Scientists at Oregon Health & Science University discovered that alpha-synuclein repairs DNA breaks in brain cells, preventing them from dying. (fiercebiotech.com)
  • The genotype of Chk2 −/− ES clones was confirmed by Southern (DNA) blotting ( Fig. 1 A), and complete loss of Chk2 protein in Chk2 −/− cells was confirmed by protein immunoblotting ( Fig. 1 B) ( 6 ). (sciencemag.org)
  • Twelve hours after 10 grays (Gy) of γ irradiation, about 90% of both Chk2 +/+ and Chk2 −/− ES cells were arrested with a G 2 DNA content ( Fig. 1 C). However, at later time points, substantially more Chk2 −/− cells entered G 1 and S relative to controls. (sciencemag.org)
  • Southern blot of Hind III- and Nhe I-digested genomic DNA from Chk2 +/+ (+/+), Chk2 +/ − (+/−), and Chk2 −/− (−/−) ES cells hybridized to the 5′ flanking probe. (sciencemag.org)
  • Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. (sciencemag.org)
  • Because cancer cells are typically not defective in DNA DSB repair, these results suggested a continuous cycle of DNA DSB formation and repair ( 1 , 2 ). (sciencemag.org)
  • C. F. Arlett and A. R. Lehmann, Human disorders showing increased sensitivity to the induction of genetic damage, Ann. (springer.com)
  • It was during one of these studies, which examined genetic damage late in the life of a B cell, that they came across chromosomal breaks that could not be explained. (eurekalert.org)
  • Over 2,500 strains of the bacteria exists with somewhere closer to 100 causing the majority of foodborne illness, meaning in theory, plenty of types of salmonella-induced food poisoning may get you sick without damaging your genetic material - something to stay positive about next time your puking into the toilet. (foodandwine.com)
  • Transposons are DNA segments that move around and alter genetic information by inserting themselves in new positions. (news-medical.net)
  • Exogen Biotechnology, a Berkeley, Calif.-based tech start-up, wants more than people's money to fund its genetic research-it also wants their DNA. (scientificamerican.com)
  • Afterwards they used chromosome analysis and DNA sequencing to study the genetic damage caused by a harmful chemical (known as acetaldehyde) produced when the body processes alcohol. (rt.com)
  • DARMSTADT, Germany , Jan. 24, 2019 /CNW/ - Merck, a leading science and technology company, today announced that it has entered into an exclusive licensing agreement with Vertex Pharmaceuticals Incorporated, Boston , USA (NASDAQ: VRTX), for two DNA-dependent protein kinase (DNA-PK) inhibitors - M9831 (formerly known as VX-984) and an additional pre-clinical compound - in the field of gene editing for six specific genetic disease indications. (newswire.ca)
  • We are rapidly advancing our leading-edge DDR portfolio in oncology and are delighted to see the potential benefit of DNA-PK in genetic diseases through the enhancement of CRISPR/Cas9-mediated gene editing. (newswire.ca)
  • This collaboration licenses two compounds to study the potential DNA-PK-inhibitor-mediated enhancement of gene editing for the treatment of six genetic diseases included in the license grant to Vertex. (newswire.ca)
  • The primary cause of cancer initiation and progression is the accumulation of mutations in the genetic material of a cell (its DNA) over time. (aacr.org)
  • This phenomenon implicated the mismatch repair (MMR) system in the processing of Me G. Unfortunately, this genetic evidence yielded no mechanistic insight as to the type of damage that was addressed by MMR or how it led to cell death. (genetics.org)
  • But, the experimental results show that treatment with mushroom is better than treatment with amaryl in case of genetic changes (DNA fragmentation, disappear of some base pairs and chromosome aberrations. (scirp.org)
  • The aggressive oxygen compounds destroy genetic material , resulting in what are referred to as harmful 8-oxo-guanine base mutations in the DNA. (medicalxpress.com)
  • It has been known that when genetic abnormalities occur, the cell cycle is halted so that the cell has time to fix the damage before the DNA is replicated. (scienceblog.com)
  • 2020) Elevated Temperatures Cause Transposon-Associated DNA Damage in C. elegans Spermatocytes. (news-medical.net)
  • Homologous recombination (HR) is a DNA metabolic process found in all forms of life that provides high-fidelity, template-dependent repair or tolerance of complex DNA damages including DNA gaps, DNA double-stranded breaks (DSBs), and DNA interstrand crosslinks (ICLs). (nature.com)
  • It is presumed to be even slower for double-stranded DNA in conditions of the nucleus. (wikipedia.org)
  • She and her team examined the genotoxicity of silica and C60 fullerene nanoparticle suspensions using the alkaline single-cell gel electrophoresis assay (Comet assay) to quantify breaks in single and double stranded DNA. (phys.org)
  • As originally reported by Alzforum at a Keystone Symposium in February, Li-Huei Tsai and colleagues at MIT found that the protein FUS partners with histone deacetylase 1 (HDAC1) to patch up double-stranded DNA breaks. (alzforum.org)
  • The findings, published in the journal Nature Biotechnology on Monday, have safety implications for gene therapies that are being developed using CRISPR/Cas9 - a type of molecular scissor technology that can be used to edit DNA. (reuters.com)
  • Failure to fix DNA breaks in our genome can impact our ability to enjoy a healthy life at an old age, as well as leave us vulnerable to neurological diseases like motor neuron disease," study co-author Sherif El-Khamisy, professor of molecular biology and biotechnology at the University of Sheffield in Britain, said in a news release. (upi.com)
  • How exactly alcohol causes damage to us is controversial," study coauthor Ketan Patel of the Medical Research Council Laboratory of Molecular Biology tells The Guardian . (the-scientist.com)
  • John Petrini, Chair of the Molecular Biology Program at the Sloan Kettering Institute, studies the biology of DNA repair. (mskcc.org)
  • John Petrini , Chair of the Molecular Biology Program at SKI, is a world expert on the mechanics of DNA repair, a topic with direct relevance to cancer. (mskcc.org)
  • Together with the University of Oxford, Enni Markkanen, a veterinarian in the working group of Prof. Ulrich Hübscher from the Institute of Veterinary Biochemistry and Molecular Biology at the University of Zurich has decoded and characterized the repair mechanism for the mutated DNA bases. (medicalxpress.com)
  • Despite these successes and the clear importance of DNA damage repair, we do not have a complete molecular understanding of this process. (fredhutch.org)
  • Both molecules were acquired in a licensing agreement from Vertex in 2017, and are part of Merck's broad portfolio of DNA Damage Response (DDR) inhibitors. (newswire.ca)
  • SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. (jci.org)
  • Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. (sciencemag.org)
  • Kanungo J . DNA-dependent protein kinase and DNA repair: relevance to Alzheimer's disease . (alzforum.org)
  • As the level of DNA damage increases, the level of phospho-Histone H2A.X (also known as γH2AX) increases, accumulating at the sites of DNA damage. (luminexcorp.com)
  • Using an imaging tool they developed, they demonstrated that alpha-synuclein traveled to sites of DNA damage in a living mouse cortex. (fiercebiotech.com)
  • 2009. Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. (springer.com)
  • In the presence of damaged DNA for instance, the p53 protein is activated by protein phosphorylation as a master guardian that activates cell cycle checkpoints and triggers cell cycle arrest to provide time for the DNA damage to be repaired. (medgadget.com)
  • ATR senses single-strand DNA breaks and DNA cross-linking and phosphorylates and activates the checkpoint protein Chk1. (jci.org)
  • DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. (mit.edu)
  • Recent theoretical studies, however, suggest that intense THz pulses of picosecond (one trillionth of a second) duration may directly affect DNA by amplifying natural vibrations (the so-called "breathing" mode) of the hydrogen bonds that bind together the two strands of DNA. (businesswire.com)
  • As a result, "bubbles" or openings in DNA strands can form. (businesswire.com)
  • DNA forms 2 long strands that wind around each other to form a double helix. (nih.gov)
  • Nucleotides are assembled into the strands by machinery that includes the enzyme DNA polymerase. (nih.gov)
  • A team led by Dr. Samuel Wilson at NIH's National Institute of Environmental Health Sciences (NIEHS) set out to determine how DNA polymerase inserts damaged nucleotides when assembling DNA strands. (nih.gov)
  • With either pairing, the oxidized nucleotide causes a nick-an opening between the 2 DNA strands. (nih.gov)
  • A key step in repairing DNA is the short resection of DNA strands at the site of damage. (fredhutch.org)
  • The amyotrophic lateral sclerosis gene FUS mends broken DNA strands, according to a paper in the September 15 Nature Neuroscience online. (alzforum.org)
  • In addition, the efficacy of chemotherapeutic drugs depends not only on their ability to induce DNA damage but also on the cell's ability to detect and respond to DNA damage [ 6 ]. (hindawi.com)
  • However, dysregulation of DNA damage sensing can also yield an increased mutation rate, potentially causing uncontrolled cell growth and cancer. (qiagen.com)
  • Whether this test result will give the individual knowledge of how to behave or what to expect in life, we don't have the slightest idea about that at the moment," says Lawrence Loeb, a DNA mutation expert at the University of Washington. (scientificamerican.com)
  • The notion that the clock regulates DNA-damage input and that mutation can affect the clock as well as the cell cycle is novel. (rxpgnews.com)
  • Age-associated changes in DNA repair and mutation rates (L. Grossman, S.-I. Moriwaki, S. Ray, R.E. Tarone, Qingyi Wei, K.H. Kraemer). (elsevier.com)
  • [2] . Most melanoma do not carry a UV-signature mutation and are therefore caused by the indirect DNA damage . (wikidoc.org)
  • Impaired mismatch binding can cause an instability in DNA microsatellite regions that comprise repeated dinucleotides. (nih.gov)
  • Microsatellite DNA instability is common in familial and sporadic colon carcinomas as well as in a number of other tumours. (nih.gov)
  • DNA instability, telomere dynamics, and cell transformation (R.J. Shmookler Reis, M.A. Shammas). (elsevier.com)
  • This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. (sciencemag.org)
  • Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations. (sciencemag.org)
  • In synapsis, DNA strand invasion by the Rad51-ssDNA filament generates a D-loop (step 3). (nature.com)
  • In synthesis-dependent strand annealing (SDSA, steps 4a - 5a - 6a), the invading strand is disengaged after DNA synthesis and annealed with the second end, leading to localized conversion without crossover. (nature.com)
  • Enzymes involved in base-excision, nucleotide excision, mismatch, double-strand break, and other DNA repair processes all respond in a pre- and post-transcriptionally regulated fashion to DNA damage. (qiagen.com)
  • The upper row is immediately following the pulse when the strand of DNA is broken. (businesswire.com)
  • The increase in the amount of phosphorylated H2AX in tissues exposed to intense THz pulses compared to unexposed controls indicated that DNA double strand breaks were indeed induced by intense THz pulses," observed Titova. (businesswire.com)
  • Intriguingly, the interplay between hMSH4 and hMof manipulates the outcomes of nonhomologous end joining (NHEJ)-mediated DNA double strand break (DSB) repair and thereby controls cell survival in response to IR. (mdpi.com)
  • As a result, the damaged nucleotide swings freely within the DNA, interfering with the repair function or causing double-strand breaks. (nih.gov)
  • When one of these oxidized nucleotides is placed into the DNA strand, it can't pair with the opposing nucleotide as usual, which leaves a gap in the DNA," Wilson says. (nih.gov)
  • But when they accumulate, the DNA polymerase adds more of them to the strand. (nih.gov)
  • Rather, it measures the overall health of people's genomes by counting double-strand breaks in their DNA. (scientificamerican.com)
  • It only took 0.1 milligrams per liter of ethyl acetate extract to inhibit DNA strand damage. (naturalnews.com)
  • These activate effector molecules, primarily ATM for double strand damage, or in its absence DNA-PKcs. (wikibooks.org)
  • DNA damage , particularly in the form of double strand breaks (DSBs) appears to play a key role in radiation-induced cell death. (wikibooks.org)
  • Cell lines from individuals with macrocephalic autism spectrum disorder have an increased number of double-strand breaks in the DNA of long neural genes. (the-scientist.com)
  • Until recently, identifying DNA double-strand breaks (DSBs) with high sensitivity was not trivial. (sciencemag.org)
  • Poly-ubiquitin chains via Lysine-63 residue (K63) of ubiquitin and linear poly-ubiquitin chains appear to play non-proteolytic functions and are involved in DNA repair, NF-κB activation, and Ras localization and signaling, etc. (frontiersin.org)
  • SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADP-ribose) polymerase 1 inhibition. (jci.org)
  • These mutations arise because the integrity of a cell's DNA is constantly under threat from errors that occur during cell multiplication and as a result of exposure to toxins, such as those in cigarette smoke, and mutagens, such as ultraviolet radiation from the sun. (aacr.org)
  • A report on this discovery, published in the current issue of the journal Nature, describes this critical early step in a cell's response to DNA damage. (scienceagogo.com)
  • Research led by biologists at the University of California, Berkeley, has found that damage to a cell's DNA sets off a chain reaction that leads to the increased expression of a marker recognized by the body's immune system. (scienceblog.com)
  • Bits of DNA were deleted, bits were broken and we even saw parts of chromosomes being moved about and rearranged. (mercola.com)
  • Greater DNA repair capacity may explain why those eating plant-based diets appear to have fewer breaks in their chromosomes as they age. (nutritionfacts.org)
  • As we age, we accumulate breaks in our DNA-actual physical breaks in our chromosomes, which may be one of the reasons we get cancer, and why our organs tend to break down as we get older. (nutritionfacts.org)
  • Scientists are warning that a water treatment widely used in developing countries could be damaging the DNA of those drinking it. (eurekalert.org)
  • Although scientists have found associations between alcohol consumption and negative health conditions such as pancreatitis and stomach cancer, what has been missing is the precise nature in which alcohol damages your body. (mercola.com)
  • Evidence of DNA-damaging compounds and DNA damage was collected by scientists based at the Masonic Cancer Center at the University of Minnesota. (genengnews.com)
  • These scientists, led by Silvia Balbo, Ph.D., assistant professor, division of environmental health sciences at the University of Minnesota, examined the saliva of e-cigarette users and found unusually high quantities of three DNA-damaging compounds, the reactive carbonyls known as formaldehyde, acrolein, and methylglyoxal. (genengnews.com)
  • Also, in comparisons of vapers and non-vapers, the scientists showed that the vapers had higher levels of DNA damage related to acrolein exposure. (genengnews.com)
  • The scientists obtained human saliva and oral cell samples from e-cigarette users and nonuser controls to screen reactive carbonyls and DNA adducts. (genengnews.com)
  • The scientists formed crystal complexes of DNA, polymerase, and oxidized nucleotides. (nih.gov)
  • Higher DNA damage may increase the risk of certain health problems, such as cancer, but scientists do not know enough yet to draw a direct causal line or reliable correlation. (scientificamerican.com)
  • Its Web site does not clearly indicate that scientists have not established dependable correlations between DNA damage and disease in most people (exceptions include certain rare hereditary diseases). (scientificamerican.com)
  • Reporting online at Nature Cell Biology this week, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center shows that BRIT1 connects with another protein complex to relax DNA's tight packaging at the site of the damage. (redorbit.com)
  • Scientists have discovered a protein that locates and facilitates the repair of damaged DNA. (upi.com)
  • March 9 (UPI) -- Scientists have developed a technique for repairing damaged DNA. (upi.com)
  • Until now, scientists have struggled to find ways to repair this kind of damage. (upi.com)
  • Scientists are hoping to identify ways to use TEX264 and its protein relatives to repair the DNA damage linked with disorders like cancer and ALS. (upi.com)
  • Using a newly developed highly sensitive liquid chromatography-tandem mass spectrometry method, the University of Leicester scientists say they have found clear indication that cannabis smoke damages DNA under laboratory conditions. (science20.com)
  • In their study, the scientists describe the development of a mass spectrometry method that they say provides a clear indication that cannabis smoke damages DNA under laboratory conditions. (science20.com)
  • Scientists have long wondered how the Mre11 complex executes this critical response to DNA damage. (mskcc.org)
  • He explained that 8-OH-dG is excreted in the urine when the body repairs DNA damage that occurs during normal body processes. (medicinenet.com)
  • While some damage occurs by chance, our findings suggest that drinking alcohol can increase the risk of this damage. (mercola.com)
  • Damage to DNA occurs on a daily basis, and the DDR describes the multiple ways in which DNA damage is detected and repaired. (astrazeneca.com)
  • Two key factors influence the DDR - the type of DNA damage, and when the damage occurs during the cell cycle. (astrazeneca.com)
  • Indirect DNA damage occurs when a UV-photon is absorbed in the human skin by a chromophore that does not have the ability to convert the energy into harmless heat very quickly. (wikipedia.org)
  • The direct DNA damage occurs only on locations of the body that are directly exposed to UV-radiation. (wikidoc.org)
  • Over time, such DNA damage might contribute to cancer or other diseases," Bhatti added. (medicinenet.com)
  • They indicate that damage to DNA can lead to cancer and hence one should be concerned about environmental agents that react with DNA. (springer.com)
  • 2009. DNA damage, aging, and cancer. (springer.com)
  • Mutations in the BRCA2 recombination gene cause predisposition to breast and ovarian cancer as well as Fanconi anemia, a cancer predisposition syndrome characterized by a defect in the repair of DNA interstrand crosslinks. (nature.com)
  • Microscopic images of a breast cancer cell with DNA damage. (eurekalert.org)
  • DNA Repair in Prostate Cancer: Biology and Clinical Implications. (urotoday.com)
  • 12 This DNA damage increases your risk for seven types of cancer, including breast and bowel cancer. (mercola.com)
  • although such damage can often be repaired by the cell, it can sometime remains untreated, and this increases the risk of cancer. (innovations-report.com)
  • He said that the publication had two main findings: humans evolved an inflammatory response when subjected to DNA damage, and the variation in TLR activity among humans suggests that some people are more prone to inflammation following DNA damage, for example, after receiving cancer therapy. (redorbit.com)
  • Stavros Garantziotis, a principal investigator in the Laboratory of Respiratory Biology (LRB) and co-author on the article, said that the publication had two main findings - humans evolved an inflammatory response when subjected to DNA damage, and the variation in TLR activity among humans suggests that some people are more prone to inflammation following DNA damage, for example, after receiving cancer therapy. (thaindian.com)
  • Nuclear DNA damage is a major cause of cancer, neurodegeneration, mitochondrial dysfunction, and many age-related diseases. (news-medical.net)
  • The Chen Lab has postdoctoral positions immediately available to work in the area of DNA damage repair and cancer biology. (mdanderson.org)
  • They think it will inform our understanding of how health problems such as premature aging, cancer and other diseases are linked to DNA damage caused by lifestyle and environmental factors such as smoking and exposure to ionizing radiation. (scientificamerican.com)
  • It doesn't necessarily mean that if your DNA damage is high, you're going to get cancer," says Steve Yannone, the Principle Scientist at Exogen and researcher at Lawrence Berkeley. (scientificamerican.com)
  • The accumulation of DNA damage is responsible for aging, cancer and neurological diseases like motor neuron disease, also known as ALS. (upi.com)
  • NaturalNews) Extracts from the leaf of the Stevia plant have been found to be high in antioxidants that prevent the DNA damage that leads to cancer, according to a new Indian study published in the Journal of Agricultural and Food Chemistry . (naturalnews.com)
  • DNA damage has been linked to a variety of diseases, especially cancer, reproductive problems and developmental defects. (naturalnews.com)
  • Attendees from 25 countries will discuss new research that is providing novel insights into the role of DNA repair deficiencies in cancer development and how this knowledge can provide novel approaches to cancer treatment. (aacr.org)
  • We hope that these results are just the tip of the iceberg for translating our understanding of DNA repair deficiencies in cancer into new approaches to treatment and that the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response, which is being presented in association with the Radiation Science and Medicine Working Group of the AACR , will accelerate the pace of progress in this area. (aacr.org)
  • The changes in DNA methylation we observed are reversible and some of them are currently being used as targets of cancer drugs. (scienceblog.com)
  • Deficiencies in DNA repair can lead to mutations that cause cancer. (mskcc.org)
  • DNA damage sounds bad, and indeed it can be - it's one of the main causes of cancer. (mskcc.org)
  • PNT737 targets the DNA Damage Response (DDR) network, a promising approach to treating cancer based on recent leading-edge discoveries in cancer biology,' said Dr. Nick Glover , President and CEO of ProNAi. (prnewswire.com)
  • This October in San Francisco, AstraZeneca will join the discussion at the conference by hosting a special lunch event to introduce and explain the significance of the DNA Damage Response (DDR) mechanism for the discovery of potential new cancer therapies. (astrazeneca.com)
  • DNA Damage Response Inhibition is an innovative new anti-cancer platform which could revolutionise the treatment of cancer. (astrazeneca.com)
  • If not corrected, this DNA damage could eventually lead to cancer. (astrazeneca.com)
  • A faulty DNA Damage Response system helps cancer develop, as it allows mutations that promote uncontrolled cell growth. (astrazeneca.com)
  • We expect that the DNA repair mechanism discovered here will lead to less invasive approaches in cancer therapy and that it will be possible to develop new clinical tests for the early detection of certain types of cancer. (medicalxpress.com)
  • The gene p53 suppresses cancer and inflammation in the body, and NIEHS investigators speculate that changes in p53 lead to changes in inflammation and the ability to repair DNA damage. (nih.gov)
  • The men "really laid the foundations for the whole field" of DNA repair, said Alan Ashworth, president of the cancer center at the University of California, San Francisco. (seattletimes.com)
  • Tissue studies indicate that nanoparticles, engineered materials about a billionth of a meter in size, could damage DNA and lead to cancer, according to research presented at the 2007 Annual Meeting of the American Association for Cancer Research. (phys.org)
  • The DNA damage could potentially lead to mutations and ultimately increase the risk of cancer. (phys.org)
  • Nanowerk News ) Tissue studies indicate that nanoparticles could damage DNA and lead to cancer, according to research presented at the 2007 Annual Meeting of the American Association for Cancer Research. (nanowerk.com)
  • Further understanding of the synuclein protein family's DNA repair functions could help facilitate the development of new therapeutic targets for several important forms of neurodegeneration and cancer," they wrote. (fiercebiotech.com)
  • DNA damage is a fact of life as a consequence of endogenous sources and processes as well as exogenous sources 1 . (nature.com)
  • Our genome is under constant attack by exogenous DNA insulting agents, such as UV light and chemical carcinogens, and by endogenous metabolic products, such as reactive oxidative species. (frontiersin.org)
  • DSBs, the most severe form of DNA damage, are generated by exogenous agents or endogenously generated reactive oxygen species (ROS) ( Khanna and Jackson, 2001 ). (jneurosci.org)
  • rather, it is a chemical unit subject to be attacked from a range of endogenous and environmental damaging agents. (intechopen.com)
  • Knockdown of endogenous MEF2D with a short-hairpin RNA (shRNA) increases sensitivity to etoposide-induced DNA damage and neuronal cell death. (jneurosci.org)
  • You will lead and drive a project focusing on the DNA damage response and DNA repair, in the maintenance of genome stability. (mendeley.com)
  • In response to DNA damage, ATM is autophosphorylated within a MRN multiprotein complex that binds DSBs. (frontiersin.org)
  • One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation. (sciencemag.org)
  • Are DNA DSBs continuously being generated in human cancers? (sciencemag.org)
  • And does DNA DSB formation precede the loss of p53 function, as would be expected if the DNA DSBs select for p53 inactivation? (sciencemag.org)
  • 5 While some types of DNA damage are repaired quickly, complex DNA damage takes longer to repair. (astrazeneca.com)
  • Clinical response to supraphysiological T treatment is associated with mutations in homologous recombination DNA repair genes. (jci.org)
  • These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition. (jci.org)
  • AstraZeneca is committed to investigating the potential of DNA Damage Response Inhibition across a range of tumour types. (astrazeneca.com)
  • see the Perspective by Hasty and Vijg) of mice carrying a mutant version of the DNA helicase gene XPD. (sciencemag.org)
  • Following damage, the TLRs interact with the tumor suppressor gene p53 to regulate the amount of inflammation. (redorbit.com)
  • Pre-clinical studies have shown that DNA-PK inhibitors can enhance CRISPR/Cas9-mediated gene editing. (newswire.ca)
  • Mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a kinase critical for the normal DNA damage response, cause the neurodegenerative disorder ataxia-telangiectasia (AT). (jneurosci.org)
  • The contribution of posttranscriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. (mdc-berlin.de)
  • "Our study highlights that not being able to process alcohol effectively can lead to an even higher risk of alcohol-related DNA damage and therefore certain cancers," Professor Patel noted. (rt.com)
  • The finding is important because DNA damage caused by radiation and environmental toxins can lead to mutations or cell death, and can also contribute to the development of cancers. (innovations-report.com)
  • The authors added, "It is well known that toxic substances in tobacco smoke can damage DNA and increase the risk of lung and other cancers. (science20.com)
  • Hereditary mutations in DNA damage repair genes significantly increase the risk of developing these cancers. (fredhutch.org)
  • 14 This increases their risk of acetaldehyde accumulation, triggering greater DNA damage and a flushed face. (mercola.com)
  • For example, chemical and environmental exposures during deployment may have provided the initial [harm] to mtDNA and accumulation of damage. (news-medical.net)
  • This accumulation of phospho-Histone H2A.X is often used to indicate the level of DNA damage present within the cell. (luminexcorp.com)
  • Bimolecular reactions can occur either between the excited chromophore and DNA or between the excited chromophore and another species, to produce free radicals and reactive oxygen species. (wikipedia.org)
  • These reactive chemical species can reach DNA by diffusion and the bimolecular reaction damages the DNA (oxidative stress). (wikipedia.org)
  • Reactive oxygen species are responsible for two different sorts of DNA damage , as they induce formation of both 8-oxo-G and FaPy-G," says Professor Thomas Carell of the Department of Chemistry at LMU. (phys.org)
  • But as a consequence of damage by reactive oxygen species , the guanine base may be transformed into FaPy-G, so that we get a FaPy-G:C base pair. (phys.org)
  • Viral manipulation of DNA repair and cell cycle checkpoints. (springer.com)
  • Now, in an study published online today in the journal Cell, Rockefeller University Professor Michel Nussenzweig, in collaboration with his brother André Nussenzweig at NCI and their colleagues, shows that when the ATM protein is absent, chromosomal breaks created during V(D)J recombination go unrepaired, and checkpoints that normally prevent the damaged cell from replicating are lost. (eurekalert.org)
  • Checkpoints are enabled through sensing DNA damage, transducing damage signals, and activating effectors. (aacrjournals.org)
  • The objective of this study was to examine the relationship between organophosphate (OP) pesticide exposure and oxidative stress and DNA damage. (ilo.org)
  • Compared with people who don't vape, four of the five e-cigarette users showed increased DNA damage related to acrolein exposure. (genengnews.com)
  • He has found that the DNA damage from folate deficiency is equivalent to the damage from 10 times the allowable annual exposure to ionizing radiation. (nutrition.org)
  • This may suggest that DNA damage in human skin arising from intense picosecond THz pulse exposure could be quickly and efficiently repaired, therefore minimizing the risk of carcinogenesis. (businesswire.com)
  • We aimed at investigating whether exposure to particulate matter induced changes in DNA methylation in blood from healthy subjects who were exposed to high levels of particulate matter in a foundry facility. (scienceblog.com)
  • each biomarker was related to oxidative damage to DNA. (consumeraffairs.com)
  • Antioxidant activity of CAPE in vitro can protect human sperm deoxyribonucleic acid from oxidative damage. (greenmedinfo.com)
  • Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at G2/M. We explored the relative importance of the PT DNA damage response (DDR) in kidney fibrosis by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor and upstream initiator of the DDR. (jci.org)
  • The above experimental evidence strongly argues that activation of the cell-cycle arrest induced by methylating agents requires processing of Me G-containing DNA. (genetics.org)
  • Histone doubles in content during the cell cycle at the same rate that DNA content doubles. (luminexcorp.com)
  • The maintenance of genomic integrity after DNA damage depends on the coordinated action of the DNA repair system and cell cycle checkpoint controls. (sciencemag.org)
  • E. C. Friedberg, U. K. Ehmann, and J. I. Williams, Human diseases associated with defective DNA repair, Adv. Radiat. (springer.com)
  • The Human DNA Repair RT² Profiler PCR Array profiles the expression of 84 key genes encoding the enzymes that repair damaged DNA. (qiagen.com)
  • Dr Camilla Sjögren and her research team have now shown that the cell also employs cohesion to repair damaged sister chromatids. (eurekalert.org)
  • APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response. (urotoday.com)
  • Grape seed extract were revealed to inhibit the oxidative induced DNA damage. (greenmedinfo.com)
  • Isoform D1 and isoform D2 inhibit UV-damaged DNA repair. (rcsb.org)
  • M. C. Paterson, Use of purified Lesion-recognizing enzymes to monitor DNA repair in vivo, Adv. Radiat. (springer.com)
  • FaPy-G is subsequently recognized as abnormal and is removed by DNA repair enzymes. (phys.org)
  • Thus, many DNA damage repair enzymes have evolved to be essential in eukaryotes. (fredhutch.org)
  • Once DNA breaks occur, they can eventually lead to tumors if unrepaired. (businesswire.com)
  • They counted DNA breaks in both meat-eaters and vegetarians at 25 years of age through 65. (nutritionfacts.org)
  • While the early activation events that follow DNA breaks are well elucidated, the primary signal which triggers DDR remains incompletely understood. (frontiersin.org)
  • Signalling DNA Damage, Protein Phosphorylation in Human Health Cai Huang, IntechOpen, DOI: 10.5772/50863. (intechopen.com)
  • Phosphorylation of Histone H2A.X at serine 139 is an important indicator of DNA damage. (luminexcorp.com)
  • Regulation of oxidative DNA damage repair by DNA polymerase λ and MutYH by crosstalk of phosphorylation and ubiquitination. (medicalxpress.com)
  • Together, our results show that MEF2D is a substrate for phosphorylation by ATM, thus promoting survival in response to DNA damage. (jneurosci.org)
  • We report that, in response to DNA damage, ATM associates with MEF2D and enhances its activity via phosphorylation. (jneurosci.org)
  • Here we show that both 53BP1 and NFBD1 are required for recruitment of ATR to DNA damage sites, as well as for ATR-dependent phosphorylation in response to DNA damage. (aacrjournals.org)
  • The recruitment of ATR into DNA damage sites seems to be the major regulatory mechanism that facilitates ATR-dependent phosphorylation. (aacrjournals.org)
  • But this study brings together a body of work which shows it is potentially damaging DNA, and harming reproductive success. (eurekalert.org)
  • Our study found that e-cigarette users are exposed to increased concentrations of potentially harmful levels of metals -- especially zinc -- that are correlated to oxidative DNA damage," said researcher Prue Talbot. (consumeraffairs.com)
  • DNA-PK is a key enzyme that could potentially enhance the efficacy of many commonly used DNA-damaging agents such as radiotherapy and chemotherapy. (newswire.ca)
  • These DNA transacting processes share common factors and use similar strategies to exert their function. (nih.gov)
  • New research shows that as your body processes alcohol, a transient toxic compound is produced that attacks DNA. (mercola.com)
  • Work such as this reminds us that biology is complex and there are still many things to discover - even in well-studied processes such as DNA damage repair. (fredhutch.org)
  • R. W. Hart, R. B. Setlow, and A. D. Woodhead, Evidence that pyrimidine dmers in DNA can give rise to tumors, Proc. (springer.com)
  • They found that, although results varied, more studies than they expected showed some evidence of genotoxicity, reporting effects including chromosomal aberrations, DNA fragmentation and damage to sperm. (eurekalert.org)
  • Prof Hunter said: "While none of the previous studies alone are definitive, and we can't use them to determine a safe level of consumption from this review, we consider that the balance of evidence suggests there is the chance of damage to DNA. (eurekalert.org)
  • There is an urgent need for more research on this area to determine if people drinking water treated with silver have evidence of DNA damage. (eurekalert.org)
  • Although Exogen's owners acknowledge the lack of evidence linking DNA damage to disease, its marketing approach is somewhat less forthcoming. (scientificamerican.com)
  • Hanawalt, P. C. & Spivak, G. Transcription-coupled DNA repair: two decades of progress and surprises. (nature.com)
  • The authors propose that the aging phenotype in the TTD mice is caused by unrepaired DNA damage that compromises transcription, which in turn leads to functional inactivation of critical genes and cell death. (sciencemag.org)
  • Is the Subject Area "DNA transcription" applicable to this article? (plos.org)
  • ATM associates with MEF2D after DNA damage and phosphorylates the transcription factor at four ATM consensus sites. (jneurosci.org)
  • Radiation-induced DNA damage, ultraviolet light, genotoxic stress and other intrinsic and extrinsic factors triggers a series of biochemical reactions known as DNA damage response. (bioone.org)
  • ATM activation is radiation dose dependent, in response to increasing level of radiation-induced DNA damage. (wikibooks.org)
  • The direct DNA damage leads to sunburn and it causes an increases melanin production. (wikidoc.org)
  • Working separately, the laureates broke new ground by mapping and explaining several of the ways a cell repairs its DNA, the molecule that contains our genes. (seattletimes.com)