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DNA DamageDNA RepairComet AssayAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsUltraviolet RaysDeoxyguanosineCheckpoint Kinase 2Tumor Suppressor Protein p53DNA-Binding ProteinsDNA Breaks, Double-StrandedProtein-Serine-Threonine KinasesOxidative StressCell CycleTumor Suppressor ProteinsGamma RaysApoptosisDNAMethyl MethanesulfonateHistonesMutagensNuclear ProteinsGenomic InstabilityG2 PhaseDNA ReplicationMutationPhosphorylationCell Line, TumorDNA Repair EnzymesDose-Response Relationship, RadiationDNA AdductsReactive Oxygen SpeciesCell SurvivalCell LineHydrogen PeroxideDNA BreaksRadiation ToleranceProtein KinasesPoly(ADP-ribose) PolymerasesGenes, cdcCell Cycle CheckpointsDNA Breaks, Single-StrandedSignal TransductionRad51 RecombinaseDNA GlycosylasesHeLa CellsS PhaseSaccharomyces cerevisiae ProteinsBRCA1 ProteinCells, CulturedFibroblastsMitosisCell AgingMicronucleus TestsSaccharomyces cerevisiaeCell NucleusHydroxyureaAntioxidantsDNA-Activated Protein KinaseG2 Phase Cell Cycle CheckpointsIntracellular Signaling Peptides and ProteinsChromatinAlkylating AgentsX-RaysTime FactorsReplication Protein ARecombinational DNA RepairModels, BiologicalProtein BindingDNA HelicasesOxidation-ReductionPoly Adenosine Diphosphate RiboseCell DeathRNA, Small InterferingMolecular Sequence DataSOS Response (Genetics)Proto-Oncogene Proteins c-mdm2Recombination, GeneticPyrimidine DimersDNA-Formamidopyrimidine GlycosylaseMitomycinHCT116 CellsMicronuclei, Chromosome-DefectiveUbiquitinationCyclin-Dependent Kinase Inhibitor p21TelomereNucleic Acid Synthesis InhibitorsDNA End-Joining RepairBlotting, WesternMutagenicity TestsGuanineDose-Response Relationship, DrugXeroderma Pigmentosum Group A ProteinLymphocytesDNA, FungalAtaxia TelangiectasiaOxidantsEndodeoxyribonucleasescdc25 PhosphatasesProliferating Cell Nuclear AntigenAntigens, NuclearEndonucleasesRNA InterferenceMice, KnockoutCarcinogensHomologous RecombinationGenes, p53Schizosaccharomyces pombe ProteinsBrain Damage, ChronicDNA FragmentationLipid PeroxidationBase SequenceAntineoplastic Agents7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxideCell ProliferationSchizosaccharomycesTranscription, GeneticEtoposideGene Expression RegulationExodeoxyribonucleasesMice, Inbred C57BLLinear Energy TransferUbiquitinUbiquitin-Protein LigasesTumor Cells, CulturedFlow CytometryChromosomal Proteins, Non-HistoneSpermatozoa4-Nitroquinoline-1-oxideIn Situ Nick-End LabelingSister Chromatid ExchangeGene DeletionZinostatinDNA, Single-StrandedTranscription FactorsAmino Acid SequenceMutagenesisRecQ HelicasesN-Glycosyl HydrolasesTelomeric Repeat Binding Protein 2DNA, NeoplasmDNA-(Apurinic or Apyrimidinic Site) LyaseProtein Structure, TertiaryChromatin Assembly and DisassemblyAntimutagenic AgentsS Phase Cell Cycle CheckpointsG1 PhaseCisplatinFree RadicalsXeroderma PigmentosumChromosome AberrationsSuperoxide DismutaseMicroscopy, FluorescenceEnzyme ActivationDNA-Directed DNA PolymeraseDisease Models, AnimalDoxorubicinCamptothecinFree Radical ScavengersTransfectionAntibiotics, AntineoplasticNeoplasmsRadiation-Protective AgentsGlutathioneFanconi Anemia Complementation Group D2 ProteinCatalaseEnzyme InhibitorsCell DivisionTopoisomerase I InhibitorsChromosomal InstabilityAcetylationDNA, MitochondrialCDC2 Protein KinaseAging, PrematureRNA, MessengerMethylnitronitrosoguanidineMitochondriaDown-RegulationDNA Topoisomerases, Type IGene Knockdown TechniquesFungal ProteinsSerineRad52 DNA Repair and Recombination ProteinHEK293 CellsCarrier ProteinsProtein Processing, Post-TranslationalFanconi AnemiaImmunoblottingTopoisomerase InhibitorsPlasmidsLiverImmunohistochemistryRadiation-Sensitizing AgentsRats, Sprague-DawleyAgingBiological MarkersRec A RecombinasesSkinAlkylationCricetinaeE2F1 Transcription Factor
DNA Damage: 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.DNA Repair: 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.Comet Assay: 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.Ataxia Telangiectasia Mutated Proteins: 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.Cell Cycle Proteins: 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.Ultraviolet Rays: 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.Deoxyguanosine: A nucleoside consisting of the base guanine and the sugar deoxyribose.Checkpoint Kinase 2: 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.Tumor Suppressor Protein p53: 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.DNA-Binding Proteins: 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.DNA Breaks, Double-Stranded: Interruptions in the sugar-phosphate backbone of DNA, across both strands adjacently.Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.Oxidative Stress: 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).Cell Cycle: 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.Tumor Suppressor Proteins: 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.Gamma Rays: 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.Apoptosis: 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.DNA: 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).Methyl Methanesulfonate: An alkylating agent in cancer therapy that may also act as a mutagen by interfering with and causing damage to DNA.Histones: 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.Mutagens: 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.Nuclear Proteins: 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.Genomic Instability: An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional.G2 Phase: 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.DNA Replication: The process by which a DNA molecule is duplicated.Mutation: 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.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Cell Line, Tumor: A cell line derived from cultured tumor cells.DNA Repair Enzymes: Enzymes that are involved in the reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule, which contained damaged regions.Dose-Response Relationship, Radiation: The relationship between the dose of administered radiation and the response of the organism or tissue to the radiation.DNA Adducts: The products of chemical reactions that result in the addition of extraneous chemical groups to DNA.Reactive Oxygen Species: 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.Cell Survival: 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.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Hydrogen Peroxide: 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.DNA Breaks: Interruptions in the sugar-phosphate backbone of DNA.Radiation Tolerance: 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.Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.Poly(ADP-ribose) Polymerases: 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, cdc: 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).Cell Cycle Checkpoints: 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.DNA Breaks, Single-Stranded: Interruptions in one of the strands of the sugar-phosphate backbone of double-stranded DNA.Signal Transduction: 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.Rad51 Recombinase: A Rec A recombinase found in eukaryotes. Rad51 is involved in DNA REPAIR of double-strand breaks.DNA Glycosylases: 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.HeLa Cells: 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.S Phase: 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.Saccharomyces cerevisiae Proteins: 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.BRCA1 Protein: 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, Cultured: 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.Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.Mitosis: 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.Cell Aging: 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.Micronucleus Tests: 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.Saccharomyces cerevisiae: 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.Cell Nucleus: 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)Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase.Antioxidants: 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.DNA-Activated Protein Kinase: 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.G2 Phase Cell Cycle Checkpoints: 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.Intracellular Signaling Peptides and Proteins: 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.Chromatin: 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.Alkylating Agents: 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.X-Rays: 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.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Replication Protein A: A single-stranded DNA-binding protein that is found in EUKARYOTIC CELLS. It is required for DNA REPLICATION; DNA REPAIR; and GENETIC RECOMBINATION.Recombinational DNA Repair: Repair of DNA DAMAGE by exchange of DNA between matching sequences, usually between the allelic DNA (ALLELES) of sister chromatids.Models, Biological: 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.Protein Binding: 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.DNA Helicases: 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.Oxidation-Reduction: 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).Poly Adenosine Diphosphate Ribose: A polynucleotide formed from the ADP-RIBOSE moiety of nicotinamide-adenine dinucleotide (NAD) by POLY(ADP-RIBOSE) POLYMERASES.Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability.RNA, Small Interfering: 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.Molecular Sequence Data: 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.SOS Response (Genetics): 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.Proto-Oncogene Proteins c-mdm2: 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.Recombination, Genetic: 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.Pyrimidine Dimers: 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.DNA-Formamidopyrimidine Glycosylase: A DNA repair enzyme that is an N-glycosyl hydrolase with specificity for DNA-containing ring-opened N(7)-methylguanine residues.Mitomycin: 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.HCT116 Cells: Human COLORECTAL CARCINOMA cell line.Micronuclei, Chromosome-Defective: 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.Ubiquitination: 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.Cyclin-Dependent Kinase Inhibitor p21: 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.Telomere: 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.Nucleic Acid Synthesis Inhibitors: Compounds that inhibit cell production of DNA or RNA.DNA End-Joining Repair: The repair of DOUBLE-STRAND DNA BREAKS by rejoining the broken ends of DNA to each other directly.Blotting, Western: 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.Mutagenicity Tests: Tests of chemical substances and physical agents for mutagenic potential. They include microbial, insect, mammalian cell, and whole animal tests.GuanineDose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Xeroderma Pigmentosum Group A Protein: 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.Lymphocytes: 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.DNA, Fungal: Deoxyribonucleic acid that makes up the genetic material of fungi.Ataxia Telangiectasia: 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).Oxidants: Electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (OXIDATION-REDUCTION).Endodeoxyribonucleases: 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.-.cdc25 Phosphatases: A subclass of dual specificity phosphatases that play a role in the progression of the CELL CYCLE. They dephosphorylate and activate CYCLIN-DEPENDENT KINASES.Proliferating Cell Nuclear Antigen: 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.Antigens, Nuclear: Immunologically detectable substances found in the CELL NUCLEUS.Endonucleases: 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.-.RNA Interference: 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.Mice, Knockout: 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.Carcinogens: 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.Homologous Recombination: An exchange of DNA between matching or similar sequences.Genes, p53: Tumor suppressor genes located on the short arm of human chromosome 17 and coding for the phosphoprotein p53.Schizosaccharomyces pombe Proteins: 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.Brain Damage, Chronic: 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.DNA Fragmentation: 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.Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide: 7,8,8a,9a-Tetrahydrobenzo(10,11)chryseno (3,4-b)oxirene-7,8-diol. A benzopyrene derivative with carcinogenic and mutagenic activity.Cell Proliferation: All of the processes involved in increasing CELL NUMBER including CELL DIVISION.Schizosaccharomyces: A genus of ascomycetous fungi of the family Schizosaccharomycetaceae, order Schizosaccharomycetales.Transcription, Genetic: The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.Etoposide: 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.Gene Expression Regulation: 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.Exodeoxyribonucleases: 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.Mice, Inbred C57BLLinear Energy Transfer: 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).Ubiquitin: 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.Ubiquitin-Protein Ligases: 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.Tumor Cells, Cultured: 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.Flow Cytometry: 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.Chromosomal Proteins, Non-Histone: 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.Spermatozoa: 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.4-Nitroquinoline-1-oxide: A potent mutagen and carcinogen. This compound and its metabolite 4-HYDROXYAMINOQUINOLINE-1-OXIDE bind to nucleic acids. It inactivates bacteria but not bacteriophage.In Situ Nick-End Labeling: 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.Sister Chromatid Exchange: 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.Gene Deletion: 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.Zinostatin: An enediyne that alkylates DNA and RNA like MITOMYCIN does, so it is cytotoxic.DNA, Single-Stranded: A single chain of deoxyribonucleotides that occurs in some bacteria and viruses. It usually exists as a covalently closed circle.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Amino Acid Sequence: 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.Mutagenesis: Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS.RecQ Helicases: 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.N-Glycosyl Hydrolases: A class of enzymes involved in the hydrolysis of the N-glycosidic bond of nitrogen-linked sugars.Telomeric Repeat Binding Protein 2: 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, Neoplasm: DNA present in neoplastic tissue.DNA-(Apurinic or Apyrimidinic Site) Lyase: 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.Protein Structure, Tertiary: 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.Chromatin Assembly and Disassembly: The mechanisms effecting establishment, maintenance, and modification of that specific physical conformation of CHROMATIN determining the transcriptional accessibility or inaccessibility of the DNA.Antimutagenic Agents: Agents that reduce the frequency or rate of spontaneous or induced mutations independently of the mechanism involved.S Phase Cell Cycle Checkpoints: 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.G1 Phase: 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.Cisplatin: 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.Free Radicals: 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.Xeroderma Pigmentosum: 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.Chromosome Aberrations: Abnormal number or structure of chromosomes. Chromosome aberrations may result in CHROMOSOME DISORDERS.Superoxide Dismutase: 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, Fluorescence: 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.Enzyme Activation: 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-Directed DNA Polymerase: 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.Disease Models, Animal: 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.Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.Camptothecin: 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.Free Radical Scavengers: 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.Transfection: 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.Antibiotics, Antineoplastic: Chemical substances, produced by microorganisms, inhibiting or preventing the proliferation of neoplasms.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.Radiation-Protective Agents: 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.Glutathione: 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.Fanconi Anemia Complementation Group D2 Protein: 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.Catalase: 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.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.Topoisomerase I Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASE I.Chromosomal Instability: An increased tendency to acquire CHROMOSOME ABERRATIONS when various processes involved in chromosome replication, repair, or segregation are dysfunctional.Acetylation: Formation of an acetyl derivative. (Stedman, 25th ed)DNA, Mitochondrial: Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.CDC2 Protein Kinase: 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.Aging, Premature: Changes in the organism associated with senescence, occurring at an accelerated rate.RNA, Messenger: 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.Methylnitronitrosoguanidine: A nitrosoguanidine derivative with potent mutagenic and carcinogenic properties.Mitochondria: 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)Down-Regulation: 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, Type I: 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.Gene Knockdown Techniques: 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.Fungal Proteins: Proteins found in any species of fungus.Serine: 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.Rad52 DNA Repair and Recombination Protein: A DNA-binding protein that mediates DNA REPAIR of double strand breaks, and HOMOLOGOUS RECOMBINATION.HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.Protein Processing, Post-Translational: 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.Fanconi Anemia: 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)Immunoblotting: 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.Topoisomerase Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASES.Plasmids: 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.Liver: A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents.Radiation-Sensitizing Agents: Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells.Rats, Sprague-Dawley: 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.Aging: The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.Biological Markers: 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.Rec A Recombinases: 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.Skin: The outer covering of the body that protects it from the environment. It is composed of the DERMIS and the EPIDERMIS.Alkylation: 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.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.E2F1 Transcription Factor: 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.

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)

The E3 Ubiquitin Ligase EDD Regulates S-Phase and G(2)/M DNA Damage CheckpointsThe E3 Ubiquitin Ligase EDD Regulates S-Phase and G(2)/M DNA Damage Checkpoints
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,
Frontiers | DNA Damage Response and Immune Defense: Links and Mechanisms | GeneticsFrontiers | DNA Damage Response and Immune Defense: Links and Mechanisms | Genetics
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.
Autophagy-dependent regulation of the DNA damage response protein ribonucleotide reductase 1. - Science ExchangeAutophagy-dependent regulation of the DNA damage response protein ribonucleotide reductase 1. - Science Exchange
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 ...
Human Spy1 Promotes Survival of Mammalian Cells following DNA Damage | Cancer ResearchHuman Spy1 Promotes Survival of Mammalian Cells following DNA Damage | Cancer Research
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 ...
Image-based quantitative determination of DNA damage signal reveals a threshold for G2 checkpoint activation in response to...Image-based quantitative determination of DNA damage signal reveals a threshold for G2 checkpoint activation in response to...
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
DNA Damage & Repair - QIAGENDNA Damage & Repair - QIAGEN
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, ...
Elevated DNA single-strand breakage frequencies in lymphocytes of welders exposed to chromium and nickel. : Carcinogenesis - oiElevated DNA single-strand breakage frequencies in lymphocytes of welders exposed to chromium and nickel. : Carcinogenesis - oi
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. ...
Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration - Research -...Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration - Research -...
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 ...
Checkpoint Regulation of Replication Forks in Response to DNA Damage: by Nicholas Adrian Willis"Checkpoint Regulation of Replication Forks in Response to DNA Damage: " by Nicholas Adrian Willis
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
Electrochemical Detection of Benzo[a]Pyrene-Induced DNA Damage at TP53 Oligomers : Impact of 5-Methyl Cytosine and...Electrochemical Detection of Benzo[a]Pyrene-Induced DNA Damage at TP53 Oligomers : Impact of 5'-Methyl Cytosine and...
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 ...
Interfaces Between the Detection, Signaling, and Repair of DNA Damage | ScienceInterfaces Between the Detection, Signaling, and Repair of DNA Damage | Science
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 ...
Replication protein A 32 kDa subunitReplication protein A 32 kDa subunit
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 ...
Nutrients that Prevent DNA Damage and Promote Their Repair In Order to Protect Against Disease - BioFoundationsNutrients that Prevent DNA Damage and Promote Their Repair In Order to Protect Against Disease - BioFoundations
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):. ...
Undamaged DNA transmits and enhances DNA damage checkpoint signals in early embryos<...Undamaged DNA transmits and enhances DNA damage checkpoint signals in early embryos<...
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 ...
Regulation of the DNA Damage Response and Gene Expression by the Dot1L Histone Methyltransferase and the 53Bp1 Tumour SuppressorRegulation of the DNA Damage Response and Gene Expression by the Dot1L Histone Methyltransferase and the 53Bp1 Tumour Suppressor
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 ...
PDF] MicroRNAs: new players in the DNA damage response. | Semantic ScholarPDF] MicroRNAs: new players in the DNA damage response. | Semantic Scholar
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.
Circadian rhythm and its role in malignancy | Journal of Circadian Rhythms | Full TextCircadian rhythm and its role in malignancy | Journal of Circadian Rhythms | Full Text
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 ...
Plus itPlus it
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 ...
Enhanced Phosphorylation of p53 by ATM in Response to DNA Damage | ScienceEnhanced Phosphorylation of p53 by ATM in Response to DNA Damage | Science
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 ...
Dimer exchange and cleavage specificity of the DNA damage response protein UmuD. | DocphinDimer exchange and cleavage specificity of the DNA damage response protein UmuD. | Docphin
PubMedID: 23220418 | Dimer exchange and cleavage specificity of the DNA damage response protein UmuD. | Biochimica et biophysica acta | 2/1/2013
miRNA Regulation of DNA Damage Response (Homo sapiens) - WikiPathwaysmiRNA Regulation of DNA Damage Response (Homo sapiens) - WikiPathways
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. ...
Rpd3L contributes to the DNA damage sensitivity of Saccharomyces cerevisiae checkpoint mutants | CrickRpd3L contributes to the DNA damage sensitivity of Saccharomyces cerevisiae checkpoint mutants | Crick
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. ...
Maintenance of the DNA-damage checkpoint requires DNA-damage-induced mediator protein oligomerization<...Maintenance of the DNA-damage checkpoint requires DNA-damage-induced mediator protein oligomerization<...
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 ...
Ιατρικά Άρθρα Αλέξανδρος Γ. Σφακιανάκης: 02/04/16Ιατρικά Άρθρα Αλέξανδρος Γ. Σφακιανάκης: 02/04/16
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 ...
ATM directs DNA damage responses and proteostasis via genetically separable pathways | Science SignalingATM directs DNA damage responses and proteostasis via genetically separable pathways | Science Signaling
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. ...
Cell damage - WikipediaCell damage - Wikipedia
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). ...
IJMS | Free Full-Text | Dynamic In Vivo Profiling of DNA Damage and Repair after Radiotherapy Using Canine Patients as a ModelIJMS | Free Full-Text | Dynamic In Vivo Profiling of DNA Damage and Repair after Radiotherapy Using Canine Patients as a Model
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
Jeppe Juul | Archive | ArticlesJeppe Juul | Archive | Articles
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 ...
Deregulation of DNA Damage Signal Transduction by Herpesvirus Latency-Associated M2 | Journal of VirologyDeregulation of DNA Damage Signal Transduction by Herpesvirus Latency-Associated M2 | Journal of Virology
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 ...
miRNA Regulation of DNA Damage Response (Homo sapiens) - WikiPathwaysmiRNA Regulation of DNA Damage Response (Homo sapiens) - WikiPathways
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 ...
The Mutated in Colorectal Cancer protein is a novel target of the UV-induced DNA damage checkpoint. | Garvan Institute of...The 'Mutated in Colorectal Cancer' protein is a novel target of the UV-induced DNA damage checkpoint. | Garvan Institute of...
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
Genetic Regulation of Dna2 Localization During the DNA Damage Response | G3: Genes | Genomes | GeneticsGenetic Regulation of Dna2 Localization During the DNA Damage Response | G3: Genes | Genomes | Genetics
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). ...
Aging | Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in |i|Drosophila|/i| - FigureAging | Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in |i|Drosophila|/i| - Figure
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
Aging | Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in |i|Drosophila|/i| - FigureAging | Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in |i|Drosophila|/i| - Figure
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
E2F and p53 Induce Apoptosis Independently during Drosophila Development but Intersect in the Context of DNA DamageE2F and p53 Induce Apoptosis Independently during Drosophila Development but Intersect in the Context of DNA Damage
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
DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses - Semantic ScholarDDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses - Semantic Scholar
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
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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 ...
More on Oxidative DNA Damage RepairMore on Oxidative DNA Damage Repair
Research has indicated that oxidative stress is the cause of many serious diseases such as cancer, Alzheimers, arteriosclerosis and diabetes.
Conformation and Proton Configuration of Pyrimidine Deoxynucleoside Oxidation Damage Products in Water - CaltechAUTHORSConformation and Proton Configuration of Pyrimidine Deoxynucleoside Oxidation Damage Products in Water - CaltechAUTHORS
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 & repair. - ppt video online downloadDNA damage & repair. - ppt video online download
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
The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development...The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development...
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 ...
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Glioblastoma multiforme (GBM) is the most common form of brain tumor with a poor prognosis and resistance to radiotherapy. Recent evidence suggests that glioma-initiating cells play a central role in radioresistance through DNA damage checkpoint activation and enhanced DNA repair. To investigate this in more detail, we compared the DNA damage response in nontumor forming neural progenitor cells (NPC) and glioma-initiating cells isolated from GBM patient specimens. As observed for GBM tumors, initial characterization showed that glioma-initiating cells have long-term self-renewal capacity. They express markers identical to NPCs and have the ability to form tumors in an animal model. In addition, these cells are radioresistant to varying degrees, which could not be explained by enhanced nonhomologous end joining (NHEJ). Indeed, NHEJ in glioma-initiating cells was equivalent, or in some cases reduced, as compared with NPCs. However, there was evidence for more efficient homologous recombination ...
Biomolecules | Free Full-Text | Targeting the Checkpoint to Kill Cancer CellsBiomolecules | Free Full-Text | Targeting the Checkpoint to Kill Cancer Cells
Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the presence of DNA damage and can lead to cell death. Importantly, as cancer cells exhibit increased levels of endogenous DNA damage due to an excessive replication stress, inhibiting the checkpoint kinases alone could act as a directed anti-cancer therapy. Here, we review the current status of inhibitors targeted towards the checkpoint effectors and discuss mechanisms of their actions in killing of cancer cells.
DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control | BMC Biology | Full TextDNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control | BMC Biology | Full Text
The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage. We identified a novel, bimodal switch of p53 dynamics modulated by DNA-damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53. Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also
Meyer, Joel | Duke Global Health InstituteMeyer, Joel | Duke Global Health Institute
Dr. Meyer studies the effects of genotoxic agents on human and wildlife health. He is interested in understanding the mechanisms by which environmental agents cause DNA damage, the molecular processes that organisms employ to protect prevent and repair DNA damage, and genetic differences that may lead to increased or decreased sensitivity to DNA damage. Mitochondrial DNA damage and repair are a particular focus. He studies DNA repair and other responses to DNA damage via PCR-based analysis of DNA damage and repair, genomic and systems biology approaches, and organismal-level responses.
lncRNA DINO essential to DNA damage response | lncRNA BloglncRNA DINO essential to DNA damage response | lncRNA Blog
DNA damage is a natural byproduct of cell division because it is impossible to faithfully copy each of the 3 billion nucleotides that make up our genomes without making at least a few errors. Damage can also be caused by exposure to certain chemical agents, ultraviolet light and ionizing radiation.. Most of the time these problems are recognized and quickly repaired by the cell. Thats where p53 comes in. When it is doing its job, p53 recognizes and responds to DNA damage by increasing the expression of genes involved in DNA repair and cell division. In this way it functions as a tumor suppressor. When mutated, however, p53 loses its ability to modulate the cells response to DNA damage. Mutations in p53 are among the most common causes of many types of cancer.. Chang and his collaborators found that p53 also increases the expression of DINO. DINO, in turn, binds to and stabilizes p53 in a kind of positive feedback loop, amplifying its signal throughout the nucleus.. ...
p53 (human)p53 (human)
Biological Process: autophagy; base-excision repair; cell aging; cell cycle arrest; cell differentiation; cell proliferation; cellular response to DNA damage stimulus; cellular response to gamma radiation; cellular response to glucose starvation; cellular response to heat; cellular response to hypoxia; cellular response to ionizing radiation; cellular response to reactive oxygen species; cellular response to UV; chromatin assembly; circadian behavior; determination of adult lifespan; DNA damage response, signal transduction by p53 class mediator; DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; DNA strand renaturation; entrainment of circadian clock by photoperiod; ER overload response; G1 DNA damage checkpoint; intrinsic apoptotic signaling pathway by p53 class mediator; intrinsic apoptotic signaling pathway in response to DNA damage by ...
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14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2 | Molecular Cancer Research14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2 | Molecular Cancer Research
14-3-3σ has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3σ contributes to these resistances via inhibiting apoptosis and arresting cells in G2-M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3σ causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2-M phase following DNA-damaging treatments. We showed that 14-3-3σ contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2-M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3σ-mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2-M arrest following ...
The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph <sup>-<...The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph <sup>-<...
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 ...
Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint<...Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint<...
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 ...
DNA damage and breast cancer risk<...DNA damage and breast cancer risk<...
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 , ...
Induction and repair inhibition of oxidative DNA damage by nickel(II) and cadmium(II) in mammalian cells. : Carcinogenesis - oiInduction and repair inhibition of oxidative DNA damage by nickel(II) and cadmium(II) in mammalian cells. : Carcinogenesis - oi
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 ...
Versatile DNA damage detection by the global genome nucleotide excision repair protein XPCVersatile DNA damage detection by the global genome nucleotide excision repair protein XPC
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 ...
Analysis of DNA damage in cells excreted in urine of cervical cancer patients using alkaline comet assay | Molecular...Analysis of DNA damage in cells excreted in urine of cervical cancer patients using alkaline comet assay | Molecular...
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 ...
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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 ...
Selleck Chemicals Blog-The Deubiquitinase USP9X Maintains DNA Replication Fork Stability and DNA Damage Checkpoint Responses by...Selleck Chemicals Blog-The Deubiquitinase USP9X Maintains DNA Replication Fork Stability and DNA Damage Checkpoint Responses by...
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 ...
CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response | Nature MedicineCRISPR-Cas9 genome editing induces a p53-mediated DNA damage response | Nature Medicine
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.
Comet Assay | Single Cell Gel Electrophoresis | Sigma-AldrichComet Assay | Single Cell Gel Electrophoresis | Sigma-Aldrich
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.
Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancerUnbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer
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 ...
OXIDATIVE DNA DAMAGE AND REPAIR IN CNS CELLS - Indiana University School of MedicineOXIDATIVE DNA DAMAGE AND REPAIR IN CNS CELLS - Indiana University School of Medicine
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 ...
Differential biologic effects of CPD and 6-4PP UV-induced DNA damage on the induction of apoptosis and cell-cycle arrest | BMC...Differential biologic effects of CPD and 6-4PP UV-induced DNA damage on the induction of apoptosis and cell-cycle arrest | BMC...
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
Automated Comet Assay Imaging and Dual-Mask Analysis to Determine DNA Damage on an Individual Comet Basis | July 7, 2016Automated Comet Assay Imaging and Dual-Mask Analysis to Determine DNA Damage on an Individual Comet Basis | July 7, 2016
BioTek Note applicative, 07-Jul-16, Automated Comet Assay Imaging and Dual-Mask Analysis to Determine DNA Damage on an Individual Comet Basis
Faculty Directory › UConn HealthFaculty Directory › UConn Health
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, ...
Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase | The EMBO JournalNoncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase | The EMBO Journal
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 role of MRN in the S-phase DNA damage checkpoint is independent of by Mary Elizabeth Porter-Goff and Nicholas R. Rhind"The role of MRN in the S-phase DNA damage checkpoint is independent of" by Mary Elizabeth Porter-Goff and Nicholas R. Rhind
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
北京大学医学部机构知识库(IR@PKUHSC): Study on DNA strand breaks induced by sodium nitroprusside, a nitric oxide donor, in vivo and in vitro北京大学医学部机构知识库([email protected]): Study on DNA strand breaks induced by sodium nitroprusside, a nitric oxide donor, in vivo and in vitro
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 ...
Effects of proton beams from the folded tandem ion accelerator on DNA damage in mouse leukocytes using the comet assay on...Effects of proton beams from the folded tandem ion accelerator on DNA damage in mouse leukocytes using the comet assay on...
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...
Detection of Histone H2AX Phosphorylation on Ser-139 as an Indicator of DNA Damage (DNA Double-Strand Breaks) - Current...Detection of Histone H2AX Phosphorylation on Ser-139 as an Indicator of DNA Damage (DNA Double-Strand Breaks) - Current...
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 ...
Cytogenetic analysis of human cells reveals specific patterns of DNA damage in replicative and oncogene-induced senescence<...Cytogenetic analysis of human cells reveals specific patterns of DNA damage in replicative and oncogene-induced senescence<...
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 ...
Defense mechanism to oxidative DNA damage in glial cells<...Defense mechanism to oxidative DNA damage in glial cells<...
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 ...
Genome instability - WikipediaGenome instability - Wikipedia
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, ...
Growth kinetics in MCF-7 cells modulate benzoapyrene-induced CYP1A1 up-regulation. - CLOK - Central Lancashire Online KnowledgeGrowth kinetics in MCF-7 cells modulate benzoapyrene-induced CYP1A1 up-regulation. - CLOK - Central Lancashire Online Knowledge
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 ...
ScholarWorks@CWU - Symposium Of University Research and Creative Expression (SOURCE): UV-induced DNA damage in Daphnia magna...[email protected] - Symposium Of University Research and Creative Expression (SOURCE): UV-induced DNA damage in Daphnia magna...
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
Institute of Cancer Research Repository - Morphological transformation of C3H/M2 mouse fibroblasts by, and genotoxicity of,...Institute of Cancer Research Repository - Morphological transformation of C3H/M2 mouse fibroblasts by, and genotoxicity of,...
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 ...
Frontiers | DNA Damage Response and Autophagy: A Meaningful Partnership | GeneticsFrontiers | DNA Damage Response and Autophagy: A Meaningful Partnership | Genetics
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.
CometAssay Electrophoresis Starter Kit plus Power Supply for EU (except UK Switzerland) | Technique alternative | 01011887528 -...CometAssay Electrophoresis Starter Kit plus Power Supply for EU (except UK Switzerland) | Technique alternative | 01011887528 -...
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 ...
Absence of superoxide dismutase activity causes nuclear DNA fragmentation during the aging process (Journal Article) | SciTech...Absence of superoxide dismutase activity causes nuclear DNA fragmentation during the aging process (Journal Article) | SciTech...
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 ...
DNA damage repair and telomere length in normal breast, preneoplastic lesions, and invasive cancer<...DNA damage repair and telomere length in normal breast, preneoplastic lesions, and invasive cancer<...
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, ...
Rad51 replication fork recruitment is required for DNA damage tolerance | The EMBO JournalRad51 replication fork recruitment is required for DNA damage tolerance | The EMBO Journal
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 ...
Global genome nucleotide excision repair is organized into domains that promote efficient DNA repair in chromatin -ORCAGlobal genome nucleotide excision repair is organized into domains that promote efficient DNA repair in chromatin -ORCA
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 ...
The 3′ processing factor CstF functions in the DNA repair response by Nurit Mirkin, Danae Fonseca et al."The 3′ processing factor CstF functions in the DNA repair response" by Nurit Mirkin, Danae Fonseca et al.
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.
The G1-S checkpoint in fission yeast is not a general DNA damage checkpoint | Journal of Cell ScienceThe G1-S checkpoint in fission yeast is not a general DNA damage checkpoint | Journal of Cell Science
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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ATM-dependent phosphorylation of ATF2 is required for the DNA damage response.ATM-dependent phosphorylation of ATF2 is required for the DNA damage response.
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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Strand-specific PCR of UV radiation-damaged genomic DNA revealed an essential role of DNA-PKcs in the transcription-coupled...Strand-specific PCR of UV radiation-damaged genomic DNA revealed an essential role of DNA-PKcs in the transcription-coupled...
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 ...
Novel Roles of Replication Protein A Phosphorylation in Cellular Respo by Moises A. Serrano"Novel Roles of Replication Protein A Phosphorylation in Cellular Respo" by Moises A. Serrano
Human replication protein A (RPA) is an eukaryotic single-stranded DNA binding protein directly involved in a variety of DNA metabolic pathways including replication, recombination, DNA damage checkpoints and signaling, as well as all DNA repair pathways. This project presents 2 novel roles of RPA in the cellular response to DNA damage. The first elucidates the regulation of RPA and p53 interaction by DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) in homologous recombination (HR). HR and nonhomologous end joining (NHEJ) are 2 distinct DNA double-stranded break (DSB) repair pathways. Here, we report that DNA-PK, the core component of NHEJ, partners with DNA-damage checkpoint kinases ATM, and ATR to synergistically regulate HR repair of DSBs. The regulation was accomplished through modulation of the p53-RPA interaction. We show that upon DNA damage p53 and RPA are freed from the p53-RPA complex. This is done through simultaneous phosphorylation
Research on environmental mutagenesis from young scientists - the open symposium of the Japanese Environmental Mutagen Society ...Research on environmental mutagenesis from young scientists - the open symposium of the Japanese Environmental Mutagen Society ...
Dr. Shun Matsuda reported his research on the visualization of DNA damage-response signals in cultured cells. This technology can be applied to simple and quick detection of genotoxicity. For example, DNA double-strand breaks orderly recruit several proteins and their modifications, such as phosphorylated histone H2AX, MDC1, and ATM, which coordinate DNA damage-response signals. He explained the absolute quantification of the components using mass spectrometry and how it could help to elucidate the stoichiometry and molecular mechanisms of DNA damage response.. Dr. Yoshinori Okamoto reported his research on the development of non-genotoxic tamoxifen analogs. Tamoxifen is a breast cancer drug, but one of its side effects is endometrial cancer. Based on the mechanisms of carcinogenicity with estrogenic activity and DNA adduct formations of the metabolite, new tamoxifen analogs were designed. These analogs exhibited higher anti-breast cancer potential and no DNA-adduct formation activity in animal ...
The Development of a Monoclonal Antibody Recognizing the Drosophila melanogaster Phosphorylated Histone H2A Variant (γ-H2AV) |...The Development of a Monoclonal Antibody Recognizing the Drosophila melanogaster Phosphorylated Histone H2A Variant (γ-H2AV) |...
The recognition of DNA Double Strand Breaks (DSBs) using a phospho-specific antibody to the histone 2A variant has become the gold standard assay for DNA damage detection. Here we report on the development of the first monoclonal antibody to the phospho-specific form of Drosophila H2AV and characterize the specificity of this antibody to programmed DSBs in oocytes and rereplication sites in endocycling cells by immunofluorescence assays and to DSBs resulting from irradiation in both cell culture and whole tissue by Western blot assays. These studies show that the antibody derived in the study is highly specific for this modification that occurs at DSB sites, and therefore will be a new useful tool within the Drosophila community for the study of DNA damage response, DSB repair, meiotic recombination and chemical agents that cause DNA damage. ...
Plus itPlus it
Regulatory molecules governing early cell cycle progression, such as cyclin D1/Cdk4/pRb, are frequent targets of genetic alterations in cancer (21). As such, the cell cycle regulatory pathway may represent a useful target for drug and gene therapy approaches. The flavone P276-00 has been evaluated here for antitumor activity in vitro and in vivo. In vitro evaluation was done in 16 tumor cell lines using PI assay and in 22 human tumor xenograft-derived panel using a clonogenic assay. Its antiproliferative activity was compared with cisplatin, a standard chemotherapeutic drug used in almost all advanced cancers. Cisplatin exerts its antitumor effects via the formation of DNA adducts and cross-links. Cisplatin-induced DNA damage results in cell cycle arrest, primarily at the S and G2 checkpoints, providing the opportunity for DNA damage repair before mitosis (22, 23). Unrepairable DNA damage often results in activation of the apoptotic pathway. In 16 human tumor cell lines and 22 human tumor ...
Roger A. Greenberg | Faculty | About Us | Perelman School of Medicine | Perelman School of Medicine at the University of...Roger A. Greenberg | Faculty | About Us | Perelman School of Medicine | Perelman School of Medicine at the University of...
Our work has revealed a partial molecular understanding for how BRCA1 recognizes DNA damage and competes with opposing DNA repair proteins to control genome integrity. We have demonstrated that an interaction between the BRCA1 BRCT domain and the RAP80 ubiquitin binding protein targets BRCA1 to K63-linked ubiquitin structures present at DNA damage sites. The RAP80 ubiquitin interaction motifs (UIMs) provide an ubiquitin recognition element to target the BRCA1 E3 ligase and a K63-ubiquitin specific deubiquitinating enzyme BRCC36 to DNA double strand breaks. Each of these activities is required for appropriate DNA damage checkpoint and repair responses (Sobhian et al. Science 2007; Shao et al. Genes&Dev 2009; Tang et al. Nat Struct & Mol Biol 2013; Jiang et al. Genes Dev 2015; Zeqiraj et al. Mol Cell 2015). Cancer causing BRCA1 BRCT mutants fail to interact with RAP80 and consequently demonstrate inefficient recruitment to DNA damage sites. Moreover, germline mutations in RAP80 and Abraxas are ...
Phosphorylation-dependent interactions between Crb2 and Chk1 are essential for DNA damage checkpointPhosphorylation-dependent interactions between Crb2 and Chk1 are essential for DNA damage checkpoint
In response to DNA damage, the eukaryotic genome surveillance system activates a checkpoint kinase cascade. In the fission yeast Schizosaccharomyces pombe, checkpoint protein Crb2 is essential for DNA damage-induced activation of downstream effector kinase Chk1. The mechanism by which Crb2 mediates Chk1 activation is unknown. Here, we show that Crb2 recruits Chk1 to double-strand breaks (DSBs) through a direct physical interaction. A pair of conserved SQ/TQ motifs in Crb2, which are consensus phosphorylation sites of upstream kinase Rad3, is required for Chk1 recruitment and activation. Mutating both of these motifs renders Crb2 defective in activating Chk1. Tethering Crb2 and Chk1 together can rescue the SQ/TQ mutations, suggesting that the main function of these phosphorylation sites is promoting interactions between Crb2 and Chk1. A 19-amino-acid peptide containing these SQ/TQ motifs is sufficient for Chk1 binding in vitro when one of the motifs is phosphorylated. Remarkably, the same ...
PlantPlant
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TesticleTesticle
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Cockayne syndromeCockayne syndrome
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Establishment of sister chromatid cohesionEstablishment of sister chromatid cohesion
Aspergillus unguisAspergillus unguis
Point accepted mutationPoint accepted mutation
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Bipolar disorderBipolar disorder
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Category:DNA - Simple English Wikipedia, the free encyclopediaCategory:DNA - Simple English Wikipedia, the free encyclopedia
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DNA DamageDNA RepairComet AssayAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsUltraviolet RaysDeoxyguanosineCheckpoint Kinase 2Tumor Suppressor Protein p53DNA-Binding ProteinsDNA Breaks, Double-StrandedProtein-Serine-Threonine KinasesOxidative StressCell CycleTumor Suppressor ProteinsGamma RaysApoptosisDNAMethyl MethanesulfonateHistonesMutagensNuclear ProteinsGenomic InstabilityG2 PhaseDNA ReplicationMutationPhosphorylationCell Line, TumorDNA Repair EnzymesDose-Response Relationship, RadiationDNA AdductsReactive Oxygen SpeciesCell SurvivalCell LineHydrogen PeroxideDNA BreaksRadiation ToleranceProtein KinasesPoly(ADP-ribose) PolymerasesGenes, cdcCell Cycle CheckpointsDNA Breaks, Single-StrandedSignal TransductionRad51 RecombinaseDNA GlycosylasesHeLa CellsS PhaseSaccharomyces cerevisiae ProteinsBRCA1 ProteinCells, CulturedFibroblastsMitosisCell AgingMicronucleus TestsSaccharomyces cerevisiaeCell NucleusHydroxyureaAntioxidantsDNA-Activated Protein KinaseG2 Phase Cell Cycle CheckpointsIntracellular Signaling Peptides and ProteinsChromatinAlkylating AgentsX-RaysTime FactorsReplication Protein ARecombinational DNA RepairModels, BiologicalProtein BindingDNA HelicasesOxidation-ReductionPoly Adenosine Diphosphate RiboseCell DeathRNA, Small InterferingMolecular Sequence DataSOS Response (Genetics)Proto-Oncogene Proteins c-mdm2Recombination, GeneticPyrimidine DimersDNA-Formamidopyrimidine GlycosylaseMitomycinHCT116 CellsMicronuclei, Chromosome-DefectiveUbiquitinationCyclin-Dependent Kinase Inhibitor p21TelomereNucleic Acid Synthesis InhibitorsDNA End-Joining RepairBlotting, WesternMutagenicity TestsGuanineDose-Response Relationship, DrugXeroderma Pigmentosum Group A ProteinLymphocytesDNA, FungalAtaxia TelangiectasiaOxidantsEndodeoxyribonucleasescdc25 PhosphatasesProliferating Cell Nuclear AntigenAntigens, NuclearEndonucleasesRNA InterferenceMice, KnockoutCarcinogensHomologous RecombinationGenes, p53Schizosaccharomyces pombe ProteinsBrain Damage, ChronicDNA FragmentationLipid PeroxidationBase SequenceAntineoplastic Agents7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxideCell ProliferationSchizosaccharomycesTranscription, GeneticEtoposideGene Expression RegulationExodeoxyribonucleasesMice, Inbred C57BLLinear Energy TransferUbiquitinUbiquitin-Protein LigasesTumor Cells, CulturedFlow CytometryChromosomal Proteins, Non-HistoneSpermatozoa4-Nitroquinoline-1-oxideIn Situ Nick-End LabelingSister Chromatid ExchangeGene DeletionZinostatinDNA, Single-StrandedTranscription FactorsAmino Acid SequenceMutagenesisRecQ HelicasesN-Glycosyl HydrolasesTelomeric Repeat Binding Protein 2DNA, NeoplasmDNA-(Apurinic or Apyrimidinic Site) LyaseProtein Structure, TertiaryChromatin Assembly and DisassemblyAntimutagenic AgentsS Phase Cell Cycle CheckpointsG1 PhaseCisplatinFree RadicalsXeroderma PigmentosumChromosome AberrationsSuperoxide DismutaseMicroscopy, FluorescenceEnzyme ActivationDNA-Directed DNA PolymeraseDisease Models, AnimalDoxorubicinCamptothecinFree Radical ScavengersTransfectionAntibiotics, AntineoplasticNeoplasmsRadiation-Protective AgentsGlutathioneFanconi Anemia Complementation Group D2 ProteinCatalaseEnzyme InhibitorsCell DivisionTopoisomerase I InhibitorsChromosomal InstabilityAcetylationDNA, MitochondrialCDC2 Protein KinaseAging, PrematureRNA, MessengerMethylnitronitrosoguanidineMitochondriaDown-RegulationDNA Topoisomerases, Type IGene Knockdown TechniquesFungal ProteinsSerineRad52 DNA Repair and Recombination ProteinHEK293 CellsCarrier ProteinsProtein Processing, Post-TranslationalFanconi AnemiaImmunoblottingTopoisomerase InhibitorsPlasmidsLiverImmunohistochemistryRadiation-Sensitizing AgentsRats, Sprague-DawleyAgingBiological MarkersRec A RecombinasesSkinAlkylationCricetinaeE2F1 Transcription Factor
Biomolecules | Free Full-Text | The RNA Splicing Response to DNA DamageBiomolecules | Free Full-Text | The RNA Splicing Response to DNA Damage
Oxidative DNA damage repairOxidative DNA damage repair
ProNAi Licenses Oncology Drug Targeting DNA Damage Response Checkpoint Kinase 1 (Chk1) from CRTProNAi Licenses Oncology Drug Targeting DNA Damage Response Checkpoint Kinase 1 (Chk1) from CRT
Post-doctoral Fellow in DNA damage response and repair job with New Scientist | 1374739Post-doctoral Fellow in DNA damage response and repair job with New Scientist | 1374739
Plasma induced DNA damage: Comparison with the effects of ionizing radiation (Journal Article) | SciTech ConnectPlasma induced DNA damage: Comparison with the effects of ionizing radiation (Journal Article) | SciTech Connect
Editorial: DNA damage & immunity. - PubMed - NCBIEditorial: DNA damage & immunity. - PubMed - NCBI
Could Shift Work Damage Your DNA?Could Shift Work Damage Your DNA?
DNA damage | Open LibraryDNA damage | Open Library
Cell umbrella protects stem cells from DNA damageCell umbrella protects stem cells from DNA damage
DNA damage repair: anytime, anywhere? - PubMed - NCBIDNA damage repair: anytime, anywhere? - PubMed - NCBI
DNA Damage and Carcinogenesis | SpringerLinkDNA Damage and Carcinogenesis | SpringerLink
Polyomavirus interaction with the DNA damage response | SpringerLinkPolyomavirus interaction with the DNA damage response | SpringerLink
DNA Damage, Neurodegeneration, and Synaptic PlasticityDNA Damage, Neurodegeneration, and Synaptic Plasticity
DNA damage detection in nucleosomes involves DNA register shifting | NatureDNA damage detection in nucleosomes involves DNA register shifting | Nature
Common water treatments could damage DNA | EurekAlert! Science NewsCommon water treatments could damage DNA | EurekAlert! Science News
Environmental DNA Damage May Drive Human Mutation - Scientific AmericanEnvironmental DNA Damage May Drive Human Mutation - Scientific American
Cellular Responses to Cisplatin-Induced DNA DamageCellular Responses to Cisplatin-Induced DNA Damage
Checking on DNA damage in S phaseChecking on DNA damage in S phase
CRISPR gene editing can cause risky collateral DNA damage: study - ReutersCRISPR gene editing can cause risky collateral DNA damage: study - Reuters
Damaged DNA [image] | EurekAlert! Science NewsDamaged DNA [image] | EurekAlert! Science News
DNA Damage ArticlesDNA Damage Articles
DNA damage tolerance, mismatch repair and genome instabilityDNA damage tolerance, mismatch repair and genome instability
How Alcohol Damages Your DNAHow Alcohol Damages Your DNA
DNA Damage Pathways Revealed | Science SignalingDNA Damage Pathways Revealed | Science Signaling
DNA Damage and Aging | Science SignalingDNA Damage and Aging | Science Signaling
Carbon Nanotubes May Damage DNA | MedgadgetCarbon Nanotubes May Damage DNA | Medgadget
Underground air might cause DNA damageUnderground air might cause DNA damage
DNA Damage & Repair - QIAGENDNA Damage & Repair - QIAGEN
Signalling DNA Damage | IntechOpenSignalling DNA Damage | IntechOpen
Direct DNA damage - WikipediaDirect DNA damage - Wikipedia
Indirect DNA damage - WikipediaIndirect DNA damage - Wikipedia
Fallujah battle toxic legacy: Damage done to DNA - RT Op-EdgeFallujah battle toxic legacy: 'Damage done to DNA' - RT Op-Edge
Beyond immuno-oncology, AstraZeneca builds up DNA damage drugs | Fox NewsBeyond immuno-oncology, AstraZeneca builds up 'DNA damage' drugs | Fox News
NIH Investigators Find Link Between DNA Damage And Immune Response - RedorbitNIH Investigators Find Link Between DNA Damage And Immune Response - Redorbit
Vaping Exposes Users to Reactive Carbonyls, Causes DNA DamageVaping Exposes Users to Reactive Carbonyls, Causes DNA Damage
AnatomyOrganismsDiseasesChemicals and DrugsAnalytical, Diagnostic and Therapeutic Techniques and EquipmentPhenomena and ProcessesDisciplines and OccupationsInformation ScienceHealth Care
DNA DamageDNA RepairComet AssayAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsUltraviolet RaysDeoxyguanosineCheckpoint Kinase 2Tumor Suppressor Protein p53DNA-Binding ProteinsDNA Breaks, Double-StrandedProtein-Serine-Threonine KinasesOxidative StressCell CycleTumor Suppressor ProteinsGamma RaysApoptosisDNAMethyl MethanesulfonateHistonesMutagensNuclear ProteinsGenomic InstabilityG2 PhaseDNA ReplicationMutationPhosphorylationCell Line, TumorDNA Repair EnzymesDose-Response Relationship, RadiationDNA AdductsReactive Oxygen SpeciesCell SurvivalCell LineHydrogen PeroxideDNA BreaksRadiation ToleranceProtein KinasesPoly(ADP-ribose) PolymerasesGenes, cdcCell Cycle CheckpointsDNA Breaks, Single-StrandedSignal TransductionRad51 RecombinaseDNA GlycosylasesHeLa CellsS PhaseSaccharomyces cerevisiae ProteinsBRCA1 ProteinCells, CulturedFibroblastsMitosisCell AgingMicronucleus TestsSaccharomyces cerevisiaeCell NucleusHydroxyureaAntioxidantsDNA-Activated Protein KinaseG2 Phase Cell Cycle CheckpointsIntracellular Signaling Peptides and ProteinsChromatinAlkylating AgentsX-RaysTime FactorsReplication Protein ARecombinational DNA RepairModels, BiologicalProtein BindingDNA HelicasesOxidation-ReductionPoly Adenosine Diphosphate RiboseCell DeathRNA, Small InterferingMolecular Sequence DataSOS Response (Genetics)Proto-Oncogene Proteins c-mdm2Recombination, GeneticPyrimidine DimersDNA-Formamidopyrimidine GlycosylaseMitomycinHCT116 CellsMicronuclei, Chromosome-DefectiveUbiquitinationCyclin-Dependent Kinase Inhibitor p21TelomereNucleic Acid Synthesis InhibitorsDNA End-Joining RepairBlotting, WesternMutagenicity TestsGuanineDose-Response Relationship, DrugXeroderma Pigmentosum Group A ProteinLymphocytesDNA, FungalAtaxia TelangiectasiaOxidantsEndodeoxyribonucleasescdc25 PhosphatasesProliferating Cell Nuclear AntigenAntigens, NuclearEndonucleasesRNA InterferenceMice, KnockoutCarcinogensHomologous RecombinationGenes, p53Schizosaccharomyces pombe ProteinsBrain Damage, ChronicDNA FragmentationLipid PeroxidationBase SequenceAntineoplastic Agents7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxideCell ProliferationSchizosaccharomycesTranscription, GeneticEtoposideGene Expression RegulationExodeoxyribonucleasesMice, Inbred C57BLLinear Energy TransferUbiquitinUbiquitin-Protein LigasesTumor Cells, CulturedFlow CytometryChromosomal Proteins, Non-HistoneSpermatozoa4-Nitroquinoline-1-oxideIn Situ Nick-End LabelingSister Chromatid ExchangeGene DeletionZinostatinDNA, Single-StrandedTranscription FactorsAmino Acid SequenceMutagenesisRecQ HelicasesN-Glycosyl HydrolasesTelomeric Repeat Binding Protein 2DNA, NeoplasmDNA-(Apurinic or Apyrimidinic Site) LyaseProtein Structure, TertiaryChromatin Assembly and DisassemblyAntimutagenic AgentsS Phase Cell Cycle CheckpointsG1 PhaseCisplatinFree RadicalsXeroderma PigmentosumChromosome AberrationsSuperoxide DismutaseMicroscopy, FluorescenceEnzyme ActivationDNA-Directed DNA PolymeraseDisease Models, AnimalDoxorubicinCamptothecinFree Radical ScavengersTransfectionAntibiotics, AntineoplasticNeoplasmsRadiation-Protective AgentsGlutathioneFanconi Anemia Complementation Group D2 ProteinCatalaseEnzyme InhibitorsCell DivisionTopoisomerase I InhibitorsChromosomal InstabilityAcetylationDNA, MitochondrialCDC2 Protein KinaseAging, PrematureRNA, MessengerMethylnitronitrosoguanidineMitochondriaDown-RegulationDNA Topoisomerases, Type IGene Knockdown TechniquesFungal ProteinsSerineRad52 DNA Repair and Recombination ProteinHEK293 CellsCarrier ProteinsProtein Processing, Post-TranslationalFanconi AnemiaImmunoblottingTopoisomerase InhibitorsPlasmidsLiverImmunohistochemistryRadiation-Sensitizing AgentsRats, Sprague-DawleyAgingBiological MarkersRec A RecombinasesSkinAlkylationCricetinaeE2F1 Transcription Factor
ProteinsPathwaysLesionsCellularApoptosisDouble-strand breaksMutationsGenomeProteinCheckpointStrand breaksMechanismsRadiationPhosphorylationInducesCellsGeneExogenousArrestIntegrityKinaseSaccharomycesMechanismGeneticRegulationExposureInhibitionPolymeraseFociReplication forksInhibitorUltravioletAdductsReactive
Proteins6
Pathways3
Lesions4
Cellular5
Apoptosis9
Double-strand breaks4
Mutations6
Genome3
Protein13
Checkpoint16
Strand breaks1
Mechanisms2
Radiation2
Phosphorylation3
Induces1
  • Dorsal root ganglion neurons similarly regenerate when the DNA damage response is targeted in vitro and in vivo and this strategy also induces significant restoration of lost function after spinal cord injury. (royalholloway.ac.uk)
Cells6
  • Cells need a highly effective mechanism of reparation, since the integrity of the DNA is essential for cell survival and normal functioning, and the damage is occurring constantly. (anyfreepapers.com)
  • Use free sample research papers on DNA damage to learn that on the basis of known energy ties, you can calculate the typical DNA cells each day undergoing spontaneous about 10000 cases of depurinization (the loss of F or G base), 500 cases of depyrimidinization (the loss C or T base) and 160 cases of Cytidine deamination (C to T transformation). (anyfreepapers.com)
  • DNA damage poses a continuous threat to genomic integrity in mammalian cells. (asm.org)
  • Virus replication presents the host cells with large amounts of exogenous genetic material, including DNA ends and unusual structures. (asm.org)
  • To ensure inheritance of intact DNA, cells rely on checkpoints. (umassmed.edu)
  • Attenuating the DNA damage response after optic nerve injury is also neuroprotective to retinal ganglion cells and promotes dramatic regeneration of their neurites both in vitro and in vivo. (royalholloway.ac.uk)
Gene3
  • The contribution of posttranscriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. (mdc-berlin.de)
  • 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. (ecu.edu)
  • Overall, the incorporation of enzymes with a DNA hybridization interface has opened up new possibilities to utilize more biologically relevant enzymes, such as cytochrome P450s, to study of important metabolic related DNA damage processes at specific gene sequences. (ecu.edu)
Exogenous5
Arrest3
  • 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. (biomedcentral.com)
  • The analysis revealed that there was a threshold of DNA damage signal for G2 arrest, which was around 4000~5000 SOID. (biomedcentral.com)
  • We developed a novel parameter for quantitative analysis of DNA damage signal, and we determined the threshold of DNA damage signal for IR-induced G2 arrest, which was represented by 4000~5000 SOID. (biomedcentral.com)
Integrity1
Kinase4
Saccharomyces1
Mechanism3
  • Researchers in the Vetsuisse Faculty have now decoded the mechanism that repairs DNA damaged in this way. (medicalxpress.com)
  • 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)
  • 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)
Genetic1
  • Deoxyribonucleic acid, commonly known as DNA, is a molecule that carries the genetic instructions used in the growth, development, functioning and reproduction of all known living organisms. (biofoundations.org)
Regulation3
Exposure2
  • Photolyase is thought to be one reason why plants - which have hours of exposure to the sun each day - are less susceptible to UV damage than humans, who lack photolyase. (stanford.edu)
  • Cell death is relative to both the length of exposure to a harmful stimulus and the severity of the damage caused. (wikipedia.org)
Inhibition2
Polymerase1
Foci2
  • Therefore, the SOID accounts for the number, size, and fluorescence density of IR-induced foci, and the parameter reflects the flux of DNA damage signal much more accurately than foci number. (biomedcentral.com)
  • The present study emphasizes that not only the foci number but also the size of the foci must be taken into consideration for the proper quantification of DNA damage signal. (biomedcentral.com)
Replication forks1
Inhibitor1
Ultraviolet2
  • A research team at the Department of Energy's SLAC National Accelerator Laboratory is using the Linac Coherent Light Source (LCLS) to study an enzyme found in plants, bacteria and some animals that repairs DNA damage caused by the sun's ultraviolet (UV) light rays. (stanford.edu)
  • In just a few seconds, ultraviolet light from the sun can damage DNA by creating hundreds of unwanted links within DNA's double helix. (stanford.edu)
Adducts1
Reactive1
  • Aspects of the sensor optimization process will be discussed including how BP stereochemistry and epigenetic factors influence the voltammetry, the impact of myoglobin non-specific adsorption on the electrode surface, and numerous control reactions designed to show that bioactivated reactive metabolites were detected at the DNA sequence. (ecu.edu)
Accumulation of DNA Damage in Hematopoietic Stem and Progenitor Cells during Human Aging
Accumulation of DNA Damage in Hematopoietic Stem and Progenitor Cells during Human Aging (journals.plos.org)
Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34
Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34 (journals.plos.org)
PLOS ONE: BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA...
PLOS ONE: BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA... (journals.plos.org)
Human RECQ1 Is a DNA Damage Responsive Protein Required for Genotoxic Stress Resistance and Suppression of Sister Chromatid...
Human RECQ1 Is a DNA Damage Responsive Protein Required for Genotoxic Stress Resistance and Suppression of Sister Chromatid... (journals.plos.org)
A Mitotic Phosphorylation Feedback Network Connects Cdk1, Plk1, 53BP1, and Chk2 to Inactivate the G2/M DNA Damage Checkpoint
A Mitotic Phosphorylation Feedback Network Connects Cdk1, Plk1, 53BP1, and Chk2 to Inactivate the G2/M DNA Damage Checkpoint (journals.plos.org)
Three Mile Island cancer rates 'normal' | New Scientist
Three Mile Island cancer rates 'normal' | New Scientist (newscientist.com)
Neoplasm - Wikipedia
Neoplasm - Wikipedia (en.wikipedia.org)
Vaping and COPD: Is it okay or can it cause more problems?
Vaping and COPD: Is it okay or can it cause more problems? (medicalnewstoday.com)
Cancer research: Zombie genes and elephants
Cancer research: Zombie genes and elephants (medicalnewstoday.com)
Cigarette smoke may 'prime lung cells' to develop cancer
Cigarette smoke may 'prime lung cells' to develop cancer (medicalnewstoday.com)
Https://www.medicalnewstoday.com/articles/315423.php
Https://www.medicalnewstoday.com/articles/315423.php (medicalnewstoday.com)
Genotoxicity Assessment | SpringerLink
Genotoxicity Assessment | SpringerLink (link.springer.com)
MTE1 Functions with MPH1 in Double-Strand Break Repair | Genetics
MTE1 Functions with MPH1 in Double-Strand Break Repair | Genetics (genetics.org)
4D Lifetec, DNA Damage Detection and Diagnostics
4D Lifetec, DNA Damage Detection and Diagnostics (4dlifetec.com)
BioInteractive Search Results | HHMI BioInteractive
BioInteractive Search Results | HHMI BioInteractive (hhmi.org)
Fanconi Anemia FANCM/FNCM-1 and FANCD2/FCD-2 Are Required for Maintaining Histone Methylation Levels and Interact with the...
Fanconi Anemia FANCM/FNCM-1 and FANCD2/FCD-2 Are Required for Maintaining Histone Methylation Levels and Interact with the... (genetics.org)
Spermatogenesis | SpringerLink
Spermatogenesis | SpringerLink (link.springer.com)
Sgs1 Binding to Rad51 Stimulates Homology-Directed DNA Repair in Saccharomyces cerevisiae | Genetics
Sgs1 Binding to Rad51 Stimulates Homology-Directed DNA Repair in Saccharomyces cerevisiae | Genetics (genetics.org)
Cell umbrella protects stem cells from DNA damage
Cell umbrella protects stem cells from DNA damage (nature.com)
European Commission - Science for Environment Policy - News Alert - Archive - Environment and Health
European Commission - Science for Environment Policy - News Alert - Archive - Environment and Health (ec.europa.eu)
Plants & Ultraviolet Light | Garden Guides
Plants & Ultraviolet Light | Garden Guides (gardenguides.com)
Polyomavirus interaction with the DNA damage response | SpringerLink
Polyomavirus interaction with the DNA damage response | SpringerLink (link.springer.com)
Bioinformatics Jobs in San Gabriel, CA | Monster.com
Bioinformatics Jobs in San Gabriel, CA | Monster.com (monster.com)
High throughput 3D super-resolution microscopy reveals Caulobacter crescentus in vivo Z-ring organization | PNAS
High throughput 3D super-resolution microscopy reveals Caulobacter crescentus in vivo Z-ring organization | PNAS (pnas.org)
Telomeres and Telomerase in Ageing, Disease, and Cancer | SpringerLink
Telomeres and Telomerase in Ageing, Disease, and Cancer | SpringerLink (link.springer.com)
Frédéric Joliot Institute for Life Sciences - Nuclear envelope, telomeres and DNA repair
Frédéric Joliot Institute for Life Sciences - Nuclear envelope, telomeres and DNA repair (cea.fr)
Nuclear and Mitochondrial DNA Repair in Selected Eukaryotic Aging Model Systems
Nuclear and Mitochondrial DNA Repair in Selected Eukaryotic Aging Model Systems (hindawi.com)