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).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.Telangiectasis: Permanent dilation of preexisting blood vessels (CAPILLARIES; ARTERIOLES; VENULES) creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders.Telangiectasia, Hereditary Hemorrhagic: An autosomal dominant vascular anomaly characterized by telangiectases of the skin and mucous membranes and by recurrent gastrointestinal bleeding. This disorder is caused by mutations of a gene (on chromosome 9q3) which encodes endoglin, a membrane glycoprotein that binds TRANSFORMING GROWTH FACTOR BETA.Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or PERIPHERAL NERVE DISEASES. Motor ataxia may be associated with CEREBELLAR DISEASES; CEREBRAL CORTEX diseases; THALAMIC DISEASES; BASAL GANGLIA DISEASES; injury to the RED NUCLEUS; and other conditions.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.Cerebellar Ataxia: Incoordination of voluntary movements that occur as a manifestation of CEREBELLAR DISEASES. Characteristic features include a tendency for limb movements to overshoot or undershoot a target (dysmetria), a tremor that occurs during attempted movements (intention TREMOR), impaired force and rhythm of diadochokinesis (rapidly alternating movements), and GAIT ATAXIA. (From Adams et al., Principles of Neurology, 6th ed, p90)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.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.Retinal Telangiectasis: A group of rare, idiopathic, congenital retinal vascular anomalies affecting the retinal capillaries. It is characterized by dilation and tortuosity of retinal vessels and formation of multiple aneurysms, with different degrees of leakage and exudates emanating from the blood vessels.Friedreich Ataxia: An autosomal recessive disease, usually of childhood onset, characterized pathologically by degeneration of the spinocerebellar tracts, posterior columns, and to a lesser extent the corticospinal tracts. Clinical manifestations include GAIT ATAXIA, pes cavus, speech impairment, lateral curvature of spine, rhythmic head tremor, kyphoscoliosis, congestive heart failure (secondary to a cardiomyopathy), and lower extremity weakness. Most forms of this condition are associated with a mutation in a gene on chromosome 9, at band q13, which codes for the mitochondrial protein frataxin. (From Adams et al., Principles of Neurology, 6th ed, p1081; N Engl J Med 1996 Oct 17;335(16):1169-75) The severity of Friedreich ataxia associated with expansion of GAA repeats in the first intron of the frataxin gene correlates with the number of trinucleotide repeats. (From Durr et al, N Engl J Med 1996 Oct 17;335(16):1169-75)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 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.Spinocerebellar Ataxias: A group of dominantly inherited, predominately late-onset, cerebellar ataxias which have been divided into multiple subtypes based on clinical features and genetic mapping. Progressive ataxia is a central feature of these conditions, and in certain subtypes POLYNEUROPATHY; DYSARTHRIA; visual loss; and other disorders may develop. (From Joynt, Clinical Neurology, 1997, Ch65, pp 12-17; J Neuropathol Exp Neurol 1998 Jun;57(6):531-43)Radiation, Ionizing: ELECTROMAGNETIC RADIATION or particle radiation (high energy ELEMENTARY PARTICLES) capable of directly or indirectly producing IONS in its passage through matter. The wavelengths of ionizing electromagnetic radiation are equal to or smaller than those of short (far) ultraviolet radiation and include gamma and X-rays.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.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.Gait Ataxia: Impairment of the ability to coordinate the movements required for normal ambulation (WALKING) which may result from impairments of motor function or sensory feedback. This condition may be associated with BRAIN DISEASES (including CEREBELLAR DISEASES and BASAL GANGLIA DISEASES); SPINAL CORD DISEASES; or PERIPHERAL NERVOUS SYSTEM DISEASES.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.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.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 Breaks, Double-Stranded: Interruptions in the sugar-phosphate backbone of DNA, across both strands adjacently.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.Epistaxis: Bleeding from the nose.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Pyrones: Keto-pyrans.Activin Receptors, Type II: One of the two types of ACTIVIN RECEPTORS. They are membrane protein kinases belonging to the family of PROTEIN-SERINE-THREONINE KINASES. The major type II activin receptors are ActR-IIA and ActR-IIB.Arteriovenous Malformations: Abnormal formation of blood vessels that shunt arterial blood directly into veins without passing through the CAPILLARIES. They usually are crooked, dilated, and with thick vessel walls. A common type is the congenital arteriovenous fistula. The lack of blood flow and oxygen in the capillaries can lead to tissue damage in the affected areas.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.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.Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.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.Dose-Response Relationship, Radiation: The relationship between the dose of administered radiation and the response of the organism or tissue to the radiation.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.Nijmegen Breakage Syndrome: A chromosome instability syndrome resulting from a defective response to DNA double-strand breaks. In addition to characteristic FACIES and MICROCEPHALY, patients have a range of findings including RADIOSENSITIVITY, immunodeficiency, increased cancer risk, and growth retardation. Causative mutations occur in the NBS1 gene, located on human chromosome 8q21. NBS1 codes for nibrin, the key regulator protein of the R/M/N (RAD50/MRE11/NBS1) protein complex which senses and mediates cellular response to DNA DAMAGE caused by IONIZING RADIATION.Streptonigrin: Complex cytotoxic antibiotic obtained from Streptomyces flocculus or S. rufochronmogenus. It is used in advanced carcinoma and causes leukopenia.CREST Syndrome: A mild form of LIMITED SCLERODERMA, a multi-system disorder. Its features include symptoms of CALCINOSIS; RAYNAUD DISEASE; ESOPHAGEAL MOTILITY DISORDERS; sclerodactyly, and TELANGIECTASIS. When the defect in esophageal function is not prominent, it is known as CRST syndrome.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.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.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.Chromosome Breakage: A type of chromosomal aberration involving DNA BREAKS. Chromosome breakage can result in CHROMOSOMAL TRANSLOCATION; CHROMOSOME INVERSION; or SEQUENCE DELETION.Microcephaly: A congenital abnormality in which the CEREBRUM is underdeveloped, the fontanels close prematurely, and, as a result, the head is small. (Desk Reference for Neuroscience, 2nd ed.)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.Heterozygote: An individual having different alleles at one or more loci regarding a specific character.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.Chromosome Aberrations: Abnormal number or structure of chromosomes. Chromosome aberrations may result in CHROMOSOME DISORDERS.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.Infrared Rays: That portion of the electromagnetic spectrum usually sensed as heat. Infrared wavelengths are longer than those of visible light, extending into the microwave frequencies. They are used therapeutically as heat, and also to warm food in restaurants.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).Nucleic Acid Synthesis Inhibitors: Compounds that inhibit cell production of DNA or RNA.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.Cell Line, Tumor: A cell line derived from cultured tumor cells.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.Cell Line, Transformed: Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals.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.Genomic Instability: An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional.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.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.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.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.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.Aphidicolin: An antiviral antibiotic produced by Cephalosporium aphidicola and other fungi. It inhibits the growth of eukaryotic cells and certain animal viruses by selectively inhibiting the cellular replication of DNA polymerase II or the viral-induced DNA polymerases. The drug may be useful for controlling excessive cell proliferation in patients with cancer, psoriasis or other dermatitis with little or no adverse effect upon non-multiplying cells.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.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.Iron-Binding Proteins: Proteins that specifically bind to IRON.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: 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).Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Cardiac Output, High: A state of elevated cardiac output due to conditions of either increased hemodynamic demand or reduced cardiac oxygen output. These conditions may include ANEMIA; ARTERIOVENOUS FISTULA; THYROTOXICOSIS; PREGNANCY; EXERCISE; FEVER; and ANOXIA. In time, compensatory changes of the heart can lead to pathological form of high cardiac output and eventual HEART FAILURE.Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase.Activin Receptors, Type I: One of the two types of ACTIVIN RECEPTORS or activin receptor-like kinases (ALK'S). There are several type I activin receptors. The major active ones are ALK-2 (ActR-IA) and ALK-4 (ActR-IB).MorpholinesMutation, Missense: A mutation in which a codon is mutated to one directing the incorporation of a different amino acid. This substitution may result in an inactive or unstable product. (From A Dictionary of Genetics, King & Stansfield, 5th ed)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.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.Chromosome Disorders: Clinical conditions caused by an abnormal chromosome constitution in which there is extra or missing chromosome material (either a whole chromosome or a chromosome segment). (from Thompson et al., Genetics in Medicine, 5th ed, p429)Homozygote: An individual in which both alleles at a given locus are identical.Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors.Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes SMOOTH MUSCLE, stimulates CARDIAC MUSCLE, stimulates DIURESIS, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide PHOSPHODIESTERASES, antagonism of ADENOSINE RECEPTORS, and modulation of intracellular calcium handling.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.Cerebellum: The part of brain that lies behind the BRAIN STEM in the posterior base of skull (CRANIAL FOSSA, POSTERIOR). It is also known as the "little brain" with convolutions similar to those of CEREBRAL CORTEX, inner white matter, and deep cerebellar nuclei. Its function is to coordinate voluntary movements, maintain balance, and learn motor skills.Chromosomes, Human, Pair 11: A specific pair of GROUP C CHROMOSOMES of the human chromosome classification.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.Proteins: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.Syndrome: A characteristic symptom complex.Immunologic Deficiency Syndromes: Syndromes in which there is a deficiency or defect in the mechanisms of immunity, either cellular or humoral.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.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.DNA Ligases: Poly(deoxyribonucleotide):poly(deoxyribonucleotide)ligases. Enzymes that catalyze the joining of preformed deoxyribonucleotides in phosphodiester linkage during genetic processes during repair of a single-stranded break in duplex DNA. The class includes both EC 6.5.1.1 (ATP) and EC 6.5.1.2 (NAD).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.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.Mice, 129 Strain: Strains of mice arising from a parental inbred stock that was subsequently used to produce substrains of knockout and other mutant mice with targeted mutations.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.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Pedigree: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.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.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)Chromosomes, Human, Pair 14: A specific pair of GROUP D CHROMOSOMES of the human chromosome classification.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)Machado-Joseph Disease: A dominantly-inherited ATAXIA first described in people of Azorean and Portuguese descent, and subsequently identified in Brazil, Japan, China, and Australia. This disorder is classified as one of the SPINOCEREBELLAR ATAXIAS (Type 3) and has been associated with a mutation of the MJD1 gene on chromosome 14. Clinical features include progressive ataxia, DYSARTHRIA, postural instability, nystagmus, eyelid retraction, and facial FASCICULATIONS. DYSTONIA is prominent in younger patients (referred to as Type I Machado-Joseph Disease). Type II features ataxia and ocular signs; Type III features MUSCULAR ATROPHY and a sensorimotor neuropathy; and Type IV features extrapyramidal signs combined with a sensorimotor neuropathy. (From Clin Neurosci 1995;3(1):17-22; Ann Neurol 1998 Mar;43(3):288-96)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.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).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.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 Mutational Analysis: Biochemical identification of mutational changes in a nucleotide sequence.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.Retinal DiseasesRecombination, 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.HCT116 Cells: Human COLORECTAL CARCINOMA cell line.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.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.Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue.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.Gene Rearrangement, T-Lymphocyte: Ordered rearrangement of T-cell variable gene regions coding for the antigen receptors.Chromosomal Instability: An increased tendency to acquire CHROMOSOME ABERRATIONS when various processes involved in chromosome replication, repair, or segregation are dysfunctional.Leucine Zippers: DNA-binding motifs formed from two alpha-helixes which intertwine for about eight turns into a coiled coil and then bifurcate to form Y shaped structures. Leucines occurring in heptad repeats end up on the same sides of the helixes and are adjacent to each other in the stem of the Y (the "zipper" region). The DNA-binding residues are located in the bifurcated region of the Y.Angiodysplasia: Acquired degenerative dilation or expansion (ectasia) of normal BLOOD VESSELS, often associated with aging. They are isolated, tortuous, thin-walled vessels and sources of bleeding. They occur most often in mucosal capillaries of the GASTROINTESTINAL TRACT leading to GASTROINTESTINAL HEMORRHAGE and ANEMIA.Trinucleotide Repeat Expansion: An increased number of contiguous trinucleotide repeats in the DNA sequence from one generation to the next. The presence of these regions is associated with diseases such as FRAGILE X SYNDROME and MYOTONIC DYSTROPHY. Some CHROMOSOME FRAGILE SITES are composed of sequences where trinucleotide repeat expansion occurs.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.Phosphatidylinositol 3-Kinases: Phosphotransferases that catalyzes the conversion of 1-phosphatidylinositol to 1-phosphatidylinositol 3-phosphate. Many members of this enzyme class are involved in RECEPTOR MEDIATED SIGNAL TRANSDUCTION and regulation of vesicular transport with the cell. Phosphatidylinositol 3-Kinases have been classified both according to their substrate specificity and their mode of action within the cell.Topoisomerase I Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASE I.Translocation, Genetic: A type of chromosome aberration characterized by CHROMOSOME BREAKAGE and transfer of the broken-off portion to another location, often to a different chromosome.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.Karyotyping: Mapping of the KARYOTYPE of a cell.Radiation-Sensitizing Agents: Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells.Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins.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.Intracranial Arteriovenous Malformations: Congenital vascular anomalies in the brain characterized by direct communication between an artery and a vein without passing through the CAPILLARIES. The locations and size of the shunts determine the symptoms including HEADACHES; SEIZURES; STROKE; INTRACRANIAL HEMORRHAGES; mass effect; and vascular steal effect.Proto-Oncogene Proteins c-abl: Non-receptor tyrosine kinases encoded by the C-ABL GENES. They are distributed in both the cytoplasm and the nucleus. c-Abl plays a role in normal HEMATOPOIESIS especially of the myeloid lineage. Oncogenic transformation of c-abl arises when specific N-terminal amino acids are deleted, releasing the kinase from negative regulation.Androstadienes: Derivatives of the steroid androstane having two double bonds at any site in any of the rings.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.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.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.Alleles: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.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.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.Telomerase: An essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic CHROMOSOMES.Mice, Mutant Strains: Mice bearing mutant genes which are phenotypically expressed in the animals.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.
p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. (1/2256)
Although broken chromosomes can induce apoptosis, natural chromosome ends (telomeres) do not trigger this response. It is shown that this suppression of apoptosis involves the telomeric-repeat binding factor 2 (TRF2). Inhibition of TRF2 resulted in apoptosis in a subset of mammalian cell types. The response was mediated by p53 and the ATM (ataxia telangiectasia mutated) kinase, consistent with activation of a DNA damage checkpoint. Apoptosis was not due to rupture of dicentric chromosomes formed by end-to-end fusion, indicating that telomeres lacking TRF2 directly signal apoptosis, possibly because they resemble damaged DNA. Thus, in some cells, telomere shortening may signal cell death rather than senescence. (+info)Requirement of ATM in phosphorylation of the human p53 protein at serine 15 following DNA double-strand breaks. (2/2256)
Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process. (+info)Atm is dispensable for p53 apoptosis and tumor suppression triggered by cell cycle dysfunction. (3/2256)
Both p53 and ATM are checkpoint regulators with roles in genetic stabilization and cancer susceptibility. ATM appears to function in the same DNA damage checkpoint pathway as p53. However, ATM's role in p53-dependent apoptosis and tumor suppression in response to cell cycle dysregulation is unknown. In this study, we tested the role of murine ataxia telangiectasia protein (Atm) in a transgenic mouse brain tumor model in which p53-mediated apoptosis results in tumor suppression. These p53-mediated activities are induced by tissue-specific inactivation of pRb family proteins by a truncated simian virus 40 large T antigen in brain epithelium. We show that p53-dependent apoptosis, transactivation, and tumor suppression are unaffected by Atm deficiency, suggesting that signaling in the DNA damage pathway is distinct from that in the oncogene-induced pathway. In addition, we show that Atm deficiency has no overall effect on tumor growth and progression in this model. (+info)GADD45 induction of a G2/M cell cycle checkpoint. (4/2256)
G1/S and G2/M cell cycle checkpoints maintain genomic stability in eukaryotes in response to genotoxic stress. We report here both genetic and functional evidence of a Gadd45-mediated G2/M checkpoint in human and murine cells. Increased expression of Gadd45 via microinjection of an expression vector into primary human fibroblasts arrests the cells at the G2/M boundary with a phenotype of MPM2 immunopositivity, 4n DNA content and, in 15% of the cells, centrosome separation. The Gadd45-mediated G2/M arrest depends on wild-type p53, because no arrest was observed either in p53-null Li-Fraumeni fibroblasts or in normal fibroblasts coexpressed with p53 mutants. Increased expression of cyclin B1 and Cdc25C inhibited the Gadd45-mediated G2/M arrest in human fibroblasts, indicating that the mechanism of Gadd45-mediated G2/M checkpoint is at least in part through modulation of the activity of the G2-specific kinase, cyclin B1/p34(cdc2). Genetic and physiological evidence of a Gadd45-mediated G2/M checkpoint was obtained by using GADD45-deficient human or murine cells. Human cells with endogenous Gadd45 expression reduced by antisense GADD45 expression have an impaired G2/M checkpoint after exposure to either ultraviolet radiation or methyl methanesulfonate but are still able to undergo G2 arrest after ionizing radiation. Lymphocytes from gadd45-knockout mice (gadd45 -/-) also retained a G2/M checkpoint initiated by ionizing radiation and failed to arrest at G2/M after exposure to ultraviolet radiation. Therefore, the mammalian genome is protected by a multiplicity of G2/M checkpoints in response to specific types of DNA damage. (+info)A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. (5/2256)
Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, and defects in checkpoints contribute to genetic instability and cancer. Much of our current understanding of checkpoints comes from genetic studies conducted in yeast. In the fission yeast Schizosaccharomyces pombe (Sp), SpRad3 is an essential component of both the DNA damage and DNA replication checkpoints. The SpChk1 and SpCds1 protein kinases function downstream of SpRad3. SpChk1 is an effector of the DNA damage checkpoint and, in the absence of SpCds1, serves an essential function in the DNA replication checkpoint. SpCds1 functions in the DNA replication checkpoint and in the S phase DNA damage checkpoint. Human homologs of both SpRad3 and SpChk1 but not SpCds1 have been identified. Here we report the identification of a human cDNA encoding a protein (designated HuCds1) that shares sequence, structural, and functional similarity to SpCds1. HuCds1 was modified by phosphorylation and activated in response to ionizing radiation. It was also modified in response to hydroxyurea treatment. Functional ATM protein was required for HuCds1 modification after ionizing radiation but not after hydroxyurea treatment. Like its fission yeast counterpart, human Cds1 phosphorylated Cdc25C to promote the binding of 14-3-3 proteins. These findings suggest that the checkpoint function of HuCds1 is conserved in yeast and mammals. (+info)Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia. (6/2256)
Mortality from cancer among 178 parents and 236 grandparents of 95 British patients with ataxia-telangiectasia was examined. For neither parents nor grandparents was mortality from all causes or from cancer appreciably elevated over that of the national population. Among mothers, three deaths from breast cancer gave rise to a standardized mortality ratio of 3.37 (95% confidence interval (CI): 0.69-9.84). In contrast, there was no excess of breast cancer in grandmothers, the standardized mortality ratio being 0.89 (95% CI: 0.18-2.59), based on three deaths. This is the largest study of families of ataxia-telangiectasia patients conducted in Britain but, nonetheless, the study is small and CIs are wide. However, taken together with data from other countries, an increased risk of breast cancer among female heterozygotes is still apparent, though lower than previously thought. (+info)The Drosophila ATM homologue Mei-41 has an essential checkpoint function at the midblastula transition. (7/2256)
BACKGROUND: Drosophila embryogenesis is initiated by 13 rapid syncytial mitotic divisions that do not require zygotic gene activity. This maternally directed cleavage phase of development terminates at the midblastula transition (MBT), at which point the cell cycle slows dramatically, membranes surround the cortical nuclei to form a cellular blastoderm, and zygotic gene expression is first required. RESULTS: We show that embryos lacking Mei-41, a Drosophila homologue of the ATM tumor suppressor, proceed through unusually short syncytial mitoses, fail to terminate syncytial division following mitosis 13, and degenerate without forming cells. A similar cleavage-stage arrest is produced by mutations in grapes, which encodes a homologue of the Checkpoint-1 kinase. We present biochemical, cytological and genetic data indicating that Mei-41 and Grapes are components of a conserved DNA-replication/damage checkpoint pathway that triggers inhibitory phosphorylation of the Cdc2 kinase and mediates resistance to replication inhibitors and DNA-damaging agents. This pathway is nonessential during postembryonic development, but it is required to terminate the cleavage stage at the MBT. Cyclins are required for Cdc2 kinase activity, and mutations in cyclin A and cyclin B bypass the requirement for mei-41 at the MBT. These mutations do not restore wild-type syncytial cell-cycle timing or the embryonic replication checkpoint, however, suggesting that Mei-41-mediated inhibition of Cdc2 has an additional essential function at the MBT. CONCLUSIONS: The Drosophila DNA-replication/damage checkpoint pathway can be activated by externally triggered DNA damage or replication defects throughout the life cycle, and under laboratory conditions this inducible function is nonessential. During early embryogenesis, however, this pathway is activated by developmental cues and is required for the transition from maternal to zygotic control of development at the MBT. (+info)Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl. (8/2256)
Cells from individuals with the recessive cancer-prone disorder ataxia telangiectasia (A-T) are hypersensitive to ionizing radiation (I-R). ATM (mutated in A-T) is a protein kinase whose activity is stimulated by I-R. c-Abl, a nonreceptor tyrosine kinase, interacts with ATM and is activated by ATM following I-R. Rad51 is a homologue of bacterial RecA protein required for DNA recombination and repair. Here we demonstrate that there is an I-R-induced Rad51 tyrosine phosphorylation, and this induction is dependent on both ATM and c-Abl. ATM, c-Abl, and Rad51 can be co-immunoprecipitated from cell extracts. Consistent with the physical interaction, c-Abl phosphorylates Rad51 in vitro and in vivo. In assays using purified components, phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. After I-R, an increase in association between Rad51 and Rad52 occurs in wild-type cells but not in cells with mutations that compromise ATM or c-Abl. Our data suggest signaling mediated through ATM, and c-Abl is required for the correct post-translational modification of Rad51, which is critical for the assembly of Rad51 repair protein complex following I-R. (+info)
ATM-dependent phosphorylation of ATF2 is required for the DNA damage response.
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KinaseDistinctKinasesApoptosisABBREVIATIONSRAD3EncodesAntibodyDisease ataxia telangiectasiaSubunitPhosphataseChk2GenesCerebellarAutosomal recessive disorder characterizedAMPKMre11-Rad5RecombinationExpressionSignaling pathwayImmunodeficiencyWorld'sCHK1NuclearSusceptibilityCheckpoint proteinsMultisystem diseaseDownstreamDouble-strandTumor protein p53Western BlotCellularDiseasesMetabolismRadiation sensitivityDamage checkpointCancerOverexpressionInteractsDeficiencyOxidative stressResiduesHuman disorderRegulationDisorderKinase activityPhosphorylatesTranscript
Kinase1
- Here, we demonstrate that the protein kinase ATM phosphorylates ATF2 on serines 490 and 498 following ionizing radiation (IR). (openrepository.com)
Distinct1
- Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. (openrepository.com)
Kinases15
- Caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases. (semanticscholar.org)
- The ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) kinases regulate cell cycle checkpoints by phosphorylating multiple substrates including the CHK1 and -2 protein kinases and p53. (semanticscholar.org)
- The complex of rapamycin with its intracellular receptor, FKBP12, interacts with RAFT1/FRAP/mTOR, the in vivo rapamycin-sensitive target and a member of the ataxia telangiectasia mutated (ATM)-related family of kinases that share homology with the catalytic domain of phosphatidylinositol 3-kinase. (pnas.org)
- In humans, the central checkpoint kinases ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related), and the RFC (replication factor C)-like checkpoint protein Rad17/RFC2-5 complex have been demonstrated to function upstream of the DNA damage response pathway for the activation of the downstream checkpoint kinase Chk1 by phosphorylation ( 3 ). (pnas.org)
- In eukaryotes , this process occurs by the addition of a phosphate group to serine , threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. (wikipedia.org)
- The structures of some autophosphorylation complexes are known from crystals of protein kinases in which the phosphorylation site (Ser, Thr, or Tyr) of one monomer in the crystal is sitting in the active site of another monomer of the crystal in a manner similar to known peptide-substrate/kinase structures. (wikipedia.org)
- The DNA damage response kinases DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated (ATM) Are stimulated by bulky adduct-containing DNA. (taleffectors.com)
- Using this cell-free system along with a wide range of pharmacological, genetic, and biochemical approaches, we recognized the DNA damage response kinases DNA -dependent protein kinase ( DNA -PK) and ataxia telangiectasia mutated (ATM) as bulky DNA damage-stimulated kinases that phosphorylate physiologically vital residues on the checkpoint proteins p53, Chk1, and RPA. (taleffectors.com)
- The binding of these kinases to damaged DNA triggers the recruitment of additional proteins, many of which become phosphorylated and activated to further transduce signals that orchestrate DNA replication, cell cycle control, transcription, repair of damage, and/or survival versus death. (frontiersin.org)
- We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH 2 -terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. (aacrjournals.org)
- In mammalian cells, MAP 3 kinases represent a family of Ser/Thr protein kinases comprised of three distinct components: ERKs, JNKs, and p38 kinase. (aacrjournals.org)
- DNA-PK also belongs to the PI3 kinase-related serine/threonine protein kinase (PI3KK) family, which also includes ATM and ATR kinases ( 1 ). (jimmunol.org)
- Thus, DNA strand breaks in cortical neurons induce rapid p53-mediated apoptosis through actions of upstream ATM and c-Abl kinases and downstream mitochondrial death proteins. (scialert.net)
- We show that ATM is intimately involved in Sp1 hyperphosphorylation during HSV-1 infection rather than individual HSV-1-encoded protein kinases. (pubfacts.com)
- D e V irgilio and L oewith 2006 ) that encode large (∼280 kDa) proteins highly conserved throughout evolution that have atypical serine/threonine protein kinase activity, yet are related to phosphatidylinositol 3-kinase protein kinases. (genetics.org)
Apoptosis7
- Upon exposure to MNNG and crosslinking agents, cells deficient in MMR proteins exhibit impaired G 2 /M cell cycle arrest, reduced activation of the p53/p73 apoptosis pathway, and resistance to the cytotoxicity of these DNA-damaging agents ( 12 - 14 ). (pnas.org)
- A gene on chromosome 19p13.3 that encodes a ubiquitously expressed serine/threonine-protein kinase which controls the activity of AMP-activated protein kinase (AMPK) family members, playing a role in various cellular processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. (thefreedictionary.com)
- The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease. (biomedsearch.com)
- Our results unveiled a previously unknown mechanism through which disruption of protein homeostasis induces caspase-8 oligomerization, activation, and apoptosis. (asm.org)
- In addition, since both the proteasome and autophagolysosome pathways function as a safeguard system to degrade misfolded or unwanted proteins, a failure within either degradation pathway leads to endoplasmic reticulum (ER) stress ( 16 ), which can induce apoptosis through upregulation of the BH3-only proteins Puma and Bim ( 44 , 46 ). (asm.org)
- One key protein that coordinates DNA repair with cell cycle progression and apoptosis is the tumor suppressor protein p53. (rupress.org)
- To further complicate the nomenclature DBC1 is a paralogue of the protein named CCAR1 (cell division cycle and apoptosis regulator protein 1) [ 27 ]. (bioscirep.org)
ABBREVIATIONS1
- In addition, DBC1 has received many other names and abbreviations including KIAA1967, P30 DBC protein, P30DBC1, NET35, DBC.1, P30 DBC2 3 and deleted in Breast Cancer Gene 1 Protein 3. (bioscirep.org)
RAD311
- We demonstrated that ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins directly phosphorylate Dbf4 in response to ionizing radiation and replication stress. (scripps.edu)
- ATR together with Rad3-related acronyms for a checkpoint kinase that is homologous to the ataxia telangiectasia mutated protein mutated in Ataxia telangiectasia and the yeast RAD3 kinase is presented. (ebscohost.com)
- We demonstrate that the ataxia telangiectasia and Rad3 related (ATR)-mediated S phase checkpoint acts as a surveillance mechanism to prevent rereplication. (rupress.org)
- Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at G2/M. We explored the relative importance of the PT DNA damage response (DDR) in kidney fibrosis by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor and upstream initiator of the DDR. (jci.org)
- Introduction Ataxia telangiectasia mutated and Rad3 Related (ATR) proteins kinase is an integral sensor of single-stranded DNA connected with stalled replication forks and fix intermediates generated during DNA fix. (bioinf.org)
- Ataxia telangiectasia-mutated (ATM)-checkpoint kinase 2 (Chk2) and ATM- and Rad3-related (ATR)-Chk1, triggered, respectively, by DNA double-strand breaks and blocked replication forks, are two major DDRs processing structurally complicated DNA damage. (pubfacts.com)
- ATR (the ATM- and Rad3-related protein kinase) also contributes to checkpoint control in eukaryotes ( 13 , 32 ). (asm.org)
- Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. (mdpi.com)
- One of the most versatile elements of the DDR is the Ataxia-telangiectasia-mutated and Rad3-related kinase (ATR). (mdpi.com)
- The function of the ATR (ataxia-telangiectasia mutated- and Rad3-related)-ATRIP (ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. (sciencemag.org)
- The ATR (ATM- and Rad3-related) protein kinase plays a central role in the cellular response to replication stress and DNA damage such as double-strand breaks (DSBs) ( 1 , 2 ). (sciencemag.org)
Encodes6
- The ataxia-telangiectasia mutated (ATM) gene encodes a nuclear 370-kd phosphoprotein known to be associated with chromosomal regions containing doublestrand breaks. (acronymfinder.com)
- Phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) encodes the p110α subunit of the mitogenic signaling protein phosphoinositide 3-kinase (PI3K). (humpath.com)
- This gene encodes a nuclear protein that is involved in V(D)J recombination and DNA repair. (genecards.org)
- The budding yeast Saccharomyces cerevisiae encodes an ortholog of the Bloom syndrome (BLM) protein that is designated Sgs1 (Small growth suppressor 1). (wikipedia.org)
- We identified a mutation in tra1 , which encodes one of two homologs of transformation/transcription domain-associated protein (TRRAP), an ATM/R-related pseudokinase that scaffolds several histone acetyltransferase (HAT) complexes. (genetics.org)
- The gene mutated in A-T, ATM (ataxia telangiectasia-mutated), encodes a 370-kD protein that is a member of a family of proteins related to phosphatidylinositol 3-kinase (PI-3-K) that have either lipid or protein kinase activity. (sciencemag.org)
Antibody2
- The analysis of two tandem mass spectra for each methyl-specific antibody resulted in the identification of over 200 new proteins that are putatively arginine-methylated. (mcponline.org)
- By Western blot this antibody detects a ~370 kDa protein representing the phospho-ATM kinase in crude lysates from gamma irradiated HeLa cells. (fishersci.com)
Disease ataxia telangiectasia3
- Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. (nih.gov)
- The work provides new insights into mechanisms of how the body fixes environmentally induced DNA damage and into the deadly neurological disease ataxia-telangiectasia (A-T), said senior author Christopher Bakkenist, assistant professor of radiation oncology, pharmacology and chemical biology at UPCI and the School of Medicine. (acronymfinder.com)
- Patients with the recessive disease ataxia telangiectasia (AT) and ATM-deficient mice exhibit immunodeficiency, genomic instability, and an increased risk for lymphoid malignancies. (nature.com)
Subunit7
- In support of this, we show that ATM interacts with the scaffolding (A) subunit of protein phosphatase 2A (PP2A), that the scaffolding and catalytic (C) subunits of PP2A interact with ATM in undamaged cells and that immunoprecipitates of ATM from undamaged cells contain PP2A-like protein phosphatase activity. (nih.gov)
- Clonogenic assays demonstrated a significant sensitization in NK314-treated cells deficient in DNA-dependent protein kinase (DNA-PK) catalytic subunit, Ku80, ataxia telangiectasia mutated (ATM), BRCA2, or XRCC3 compared with wild-type cells, indicating that both nonhomologous end-joining and homologous recombination DNA repair pathways contribute to cell survival. (aspetjournals.org)
- Initiation factor 4F complexes with these mRNAs through the interaction of its eIF-4G subunit with eIF-4E, the cap-binding protein that recognizes the N 7 -methyl-GpppN structure of the 5′ end of all nonorganellar mRNAs. (pnas.org)
- The DNA-dependent protein kinase (DNA-PK) is a cNHEJ factor that encompasses the Ku70-Ku80 (KU) heterodimer and the large DNA-PK catalytic subunit (DNA-PKcs). (jimmunol.org)
- The protein encoded by this gene is the 80-kilodalton subunit of the Ku heterodimer protein which is also known as ATP-dependant DNA helicase II or DNA repair protein XRCC5. (genecards.org)
- The XRCC5/6 dimer acts as regulatory subunit of the DNA-dependent protein kinase complex DNA-PK by increasing the affinity of the catalytic subunit PRKDC to DNA by 100-fold. (genecards.org)
- Protein phosphatase 1 and phosphatase 1 nuclear targeting subunit-dependent regulation of DNA-dependent protein kinase and non-homologous end joining. (abcam.com)
Phosphatase7
- Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A. (nih.gov)
- Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. (nih.gov)
- OA did not induce gamma-H2AX foci, suggesting that it induces ATM autophosphorylation by inactivation of a protein phosphatase rather than by inducing DNA double-strand breaks. (nih.gov)
- B ) C35ABR cells were incubated for 2 h with increasing concentrations of OA as indicated and processed as described in panel A. ( C ) The extracts shown in panel B were assayed for the percent of PP1 (light bars) or PP2A-like (dark bars) protein phosphatase activity remaining. (nih.gov)
- Cells were lysed in NETN buffer with or without protein phosphatase inhibitors as indicated. (nih.gov)
- Activation of ATM by DIM may be due, in part, to inhibition of protein phosphatase 2A, an upstream regulator of ATM. (nih.gov)
- Here, we propose the polyamine spermidine as a novel therapeutic agent in airways diseases, based on a recently identified mode of action: T-cell protein tyrosine phosphatase (TCPTP) agonism. (frontiersin.org)
Chk23
- thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. (abnova.com)
- DDR is mediated by a signal transduction cascade involving the ataxia telangiectasia mutated (ATM-) check point kinase 2 (Chk2)-p53 axis [ 8 , 9 ]. (hindawi.com)
- Furthermore, JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580 both could reverse the EA upregulation of the protein of Chk2 level, significantly. (sigmaaldrich.com)
Genes2
- As important genes in the DNA damage response pathway, comutation in the tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes may be associated with genomic instability and hypermutation. (cdc.gov)
- In fact, the dephosphorylating activity of TCPTP inhibits the signaling cascade that leads to the expression of genes involved in detachment and epithelial-to-mesenchymal transition (EMT), and increases the expression of adhesion and tight junction proteins, thereby enhancing the barrier functionality in inflammation-prone tissues. (frontiersin.org)
Cerebellar3
- Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disorder characterized by a wide range of clinical manifestations, including cerebellar ataxia, conjunctival telangiectases, recurrent sinopulmonary infections, radiosensitivity, and increased cancer susceptibility (1). (acronymfinder.com)
- It is a multisystem disease characterized by progressive cerebellar ataxia, oculocutaneous telagiectasia and immunodeficiency with defects in both cellular and humoral immunity. (ebscohost.com)
- Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by clinical manifestations that include progressive cerebellar ataxia, neuronal degeneration, hypersensitivity to ionizing radiation (IR), premature aging, hypogonadism, growth retardation, immune deficiency, and an increased risk for cancer ( 1 ). (sciencemag.org)
Autosomal recessive disorder characterized1
- Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive neurologic degeneration, immunologic deficiency, and an increased risk of lymphoid cancer. (fishersci.com)
AMPK2
- STK11 acts by phosphorylating the T-loop of AMPK family proteins, upregulating their activity. (thefreedictionary.com)
- also known as STK11) and AMP-activated protein kinase (AMPK) played a central role in this stimulation. (sigmaaldrich.com)
Mre11-Rad51
- Repair of these presumably difficult-to-rejoin breaks also requires several other proteins, including the Mre11/Rad50/NBS1 complex, the ataxia telangiectasia-mutated ATM kinase, and 53BP1. (wikipedia.org)
Recombination3
- Required for V(D)J recombination, the process by which exons encoding the antigen-binding domains of immunoglobulins and T-cell receptor proteins are assembled from individual V, (D), and J gene segments. (genecards.org)
- The normal protein may act to suppress inappropriate homologous recombination. (wikipedia.org)
- Ku is the DNA-binding component of the DNA-dependent protein kinase, and it functions together with the DNA ligase IV-XRCC4 complex in the repair of DNA double-strand break by non-homologous end joining and the completion of V(D)J recombination events. (genecards.org)
Expression12
- Hall J. The Ataxia-telangiectasia mutated gene and breast cancer: gene expression profiles and sequence variants. (medlineplus.gov)
- Moreover, western blotting and real-time PCR were used to examine the protein expression levels and the mRNA expression levels, respectively. (cancerindex.org)
- In the present study, we have examined whether DNA-PK activity correlates with radiation sensitivity of 14 esophageal cancer cell lines and whether DNA-PK activity correlates with expression of Ku70, Ku80, or DNA-PKcs protein. (aacrjournals.org)
- In mouse models, loss of DNA-PKcs ( DNA-PKcs −/− ) abrogates end processing (e.g., hairpin opening), but not end-ligation, whereas expression of the kinase-dead DNA-PKcs protein ( DNA-PKcs KD/KD ) abrogates end-ligation, suggesting a kinase-dependent structural function of DNA-PKcs during cNHEJ. (jimmunol.org)
- Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: a novel mechanism for phenotype modulation. (semanticscholar.org)
- Cell death protein expression patterns in mouse forebrain are mostly similar to cultured neurons. (scialert.net)
- Thus, a recombinant, FLAG peptide-tagged, wild-type ATM was used as a source of ATM protein, and a FLAG peptide-tagged, mutant ATM expression construct was generated in which two of the three critical amino acid residues required for catalysis were mutated (Asp 2870 → Ala and Asn 2875 → Lys) ( 13 ). (sciencemag.org)
- Here, the cell cycle distribution by flow cytometry was examined and the protein expression by the western blotting methods was analyzed. (sigmaaldrich.com)
- Since little is known about the transcriptional level of AEG-1 expression and its biological pathway in CRC the aim of the present study was to examine the relationship of AEG-1 mRNA expression, the protein level and clinicopathological variables as well as its biology pathway in CRC. (biomedcentral.com)
- AEG-1 protein expression was investigated by immunohistochemistry in paraffin-embedded materials from 74 distant normal mucosa, 107 adjacent mucosa, 158 primary tumour, 35 lymph node metastasis and 9 liver metastasis samples. (biomedcentral.com)
- In addition, the AEG-1 protein expression was elucidated in the cell lines by Western blot. (biomedcentral.com)
- Explore and order pathway-specific siRNAs, real-time PCR assays, or optimized protein expression vectors. (qiagen.com)
Signaling pathway1
- Studies with rapamycin ( 4 ), a potent immunosuppressant, have uncovered a signaling pathway that modulates protein synthesis in yeast ( 5 ) and animal cells ( 6 , 7 ). (pnas.org)
Immunodeficiency1
- Bloom syndrome and ataxia-telangiectasia are autosomal recessive human disorders characterized by immunodeficiency, genome instability and predisposition to develop cancer. (nii.ac.jp)
World's1
- Cryo-EM has enabled researchers to define the world's first protein structures for human ataxia telangiectasia mutated (ATM). (fei.com)
CHK14
- ATR senses single-strand DNA breaks and DNA cross-linking and phosphorylates and activates the checkpoint protein Chk1. (jci.org)
- However, these cells are semi-wee even when overexpressing chk1 + and accumulate inactive Wee1 protein. (genetics.org)
- Chk1 is an evolutionarily conserved protein kinase that regulates cell cycle progression in response to checkpoint activation. (asm.org)
- The phosphorylated form of Chk1 possessed higher intrinsic protein kinase activity and eluted more quickly on gel filtration columns. (asm.org)
Nuclear6
- Physiologic submicromolar concentrations of DIM protected cultured cells against radiation by a unique mechanism: DIM caused rapid activation of ataxia-telangiectasia mutated (ATM), a nuclear kinase that regulates responses to DNA damage (DDR) and oxidative stress. (nih.gov)
- In the case of small nuclear ribonucleoprotein (snRNP) particle assembly, arginine methylation by the PRMT5 methylosome ( 32 , 33 ) has been proposed to be the signal for the recognition and targeting to the SMN protein complexes ( 31 ). (mcponline.org)
- Molecularly, DDR is initiated by the rapid recruitment of several nuclear proteins involved in the repair process to the site of DNA damage to form a complex, which acts to repair DNA damage and promote cell survival. (hindawi.com)
- DBC1 (deleted in breast cancer-1) is a nuclear protein that regulates cellular metabolism. (bioscirep.org)
- DBC1 (deleted in breast cancer-1) is a nuclear protein that was originally proposed to be deleted in some breast cancers [ 1 ]. (bioscirep.org)
- DBC1 binds and regulates the function of several nuclear proteins and epigenetic modifiers such as nuclear receptors (e.g. (bioscirep.org)
Susceptibility1
- 53BP1 contains two breast cancer susceptibility gene 1 COOH terminus (BRCT) motifs, which are present in several proteins involved in DNA repair and/or DNA damage-signaling pathways. (rupress.org)
Checkpoint proteins1
- Because different DNA-damaging agents generate different DNA lesions, a key question in damage signaling is how the checkpoint proteins recognize different DNA lesions. (pnas.org)
Multisystem disease1
- DIAGNOSIS Ataxia-telangiectasia DISCUSSION Ataxia-telangiectasia (AT), also known as Louis-Bar syndrome, is a hereditary autosomal recessive progressive multisystem disease. (acronymfinder.com)
Downstream2
- ATM phosphorylates proteins instead of lipid and has many downstream targets that act as cell-cycle regulators including: P53, Mdm2, BRCA1, and SMC1. (fishersci.com)
- This is defined as the transfer of phosphoryl groups [(PO3)2-] from one molecule to another, and serves as a transfer of energy that results in the activation, or deactivation of downstream proteins. (biolegend.com)
Double-strand2
- The MRN complex, comprised of the Mre11, Rad50 and NBS1 proteins, senses DNA damage, known as double-strand breaks, within the cell. (emaxhealth.com)
- ATM gene located on chromosome 11q22-23 spanning over 160 kb of genomic DNA and produces an approximately 350 kDa protein that plays a key role in DNA damage response, especially for double-strand break [ 19 ]. (hindawi.com)
Tumor protein p531
- Association of Tumor Protein p53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patien. (cdc.gov)
Western Blot1
- At BioLegend, we offer a wide array of phospho protein-related products for use in flow cytometry, Western blot, and microscopy applications. (biolegend.com)
Cellular5
- Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). (aacrjournals.org)
- Excess ROS can overwhelm a cell's antioxidant scavenging capacity, causing oxidative damage to DNA, lipids, and proteins, as well as concomitant cellular damage ( 11 ). (rupress.org)
- The ataxia telangiectasia-mutated (ATM) protein, a member of the related phosphatidylinositol 3-like kinase family encoded by a gene responsible for the human genetic disorder ataxia telangiectasia, regulates cellular responses to DNA damage and viral infection. (pubfacts.com)
- Cellular proteins are degraded by two mechanistically connected processes: the ubiquitin-proteasomal pathway and the autophagolysosomal pathway ( 11 , 16 , 32 , 35 ). (asm.org)
- PKA (Protein Kinase-A) is a second messenger-dependent enzyme that has been implicated in a wide range of cellular processes, including transcription, metabolism, cell cycle progression and. (qiagen.com)
Diseases1
- When the MRN complex doesn't work properly, inherited human neurological diseases, such as ataxia-telangiectasia-like syndrome and Nijmegen breakage syndrome, result. (emaxhealth.com)
Metabolism1
- AKT, also known as protein kinase B (PKB) or RAS-alpha, is a ubiquitous serine/threonine kinase that plays an important role in diverse biological responses such as regulation of metabolism, cell survival, and growth. (thermofisher.com)
Radiation sensitivity2
- We investigated the relationship between DNA-dependent protein kinase (DNA-PK) activity and radiation sensitivity using 14 esophageal cancer cell lines, TE 1-14. (aacrjournals.org)
- Roles of DNA-dependent protein kinase and ATM in cell-cycle-dependent radiation sensitivity in human cells. (biomedsearch.com)
Damage checkpoint1
- A key component of the DNA damage checkpoint is ATM (ataxia telangiectasia-mutated), a 370-kDa protein kinase ( 58 ). (asm.org)
Cancer14
- Because of its central role in cell division and DNA repair, the ATM protein is of great interest in cancer research. (medlineplus.gov)
- Research suggests that people who carry one mutated copy of the ATM gene in each cell may have an increased risk of developing several other types of cancer. (medlineplus.gov)
- Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk. (medlineplus.gov)
- Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite ins. (cdc.gov)
- We have previously reported the ATM protein loss by immunohistochemistry (IHC) in 16% of human gastric cancer (GC) tissue. (cdc.gov)
- E) Immunohistochemistry of ATM protein in gastric cancer cell-lines. (cdc.gov)
- Alteration of this gene, along with dramatic downregulation of WWOX protein, is shown in the majority of invasive cancer cells. (humpath.com)
- University of Michigan researchers have discovered that a key protein in cells plays a critical role in not one, but two processes affecting the development of cancer. (emaxhealth.com)
- Most proteins involved in responding to DNA damage that can cause cancer either help detect the damage and warn the rest of the cell, or help repair the damage," says David O. Ferguson, M.D., Ph.D., the study's lead author. (emaxhealth.com)
- ATM is a key trigger protein in the DNA damage response and a prime therapeutic target in cancer research. (fei.com)
- Since cancerous cells often display elevated protein synthesis and by-product disposal, inhibition of the protein degradation pathways is an emerging approach for cancer therapy. (asm.org)
- Cancer cells, owing to their aberrant transcription/translation activity and protein disposal, may become more vulnerable to proteotoxicity. (asm.org)
- In colorectal cancer (CRC), the protein level of AEG-1 is up-regulated in tumour tissue compared to normal mucosa, showing prognostic significance. (biomedcentral.com)
- DBC1 is not to be confused with another protein named deleted in bladder cancer-1 that receives the same abbreviation. (bioscirep.org)
Overexpression1
- We demonstrate that uncontrolled DNA unwinding by minichromosome maintenance proteins upon Cdt1 overexpression is an important mechanism that leads to ssDNA accumulation and checkpoint activation. (rupress.org)
Interacts1
- Ataxia telangiectasia mutated (ATM) interacts with p400 ATPase for an efficient DNA damage response. (abcam.com)
Deficiency1
- A deficiency in DNA repair was clearly demonstrated to be an underlying cause of UV-sensitivity in XP and Cockayne syndrome, but more complex abnormalities in the processing of DNA damage induced by X-irradiation were identified in ataxia telangiectasia (AT). (scielo.br)
Oxidative stress2
- Moreover, the transcription factor Sp1 was found to bind to this region in response to oxidative stress under the regulation of ataxia telangiectasia mutated (ATM) kinase. (mdpi.com)
- Furthermore, HCV viral nucleocapsid protein, an HCV core protein, was shown to increase oxidative stress in the liver [ 7 , 8 ]. (mdpi.com)
Residues2
- The MA1-2020 immunogen is a phosphorylated synthetic peptide corresponding to the residues S(1974) L A F E E S(p) Q S T T I S S(1988) of human ATM Kinase protein. (fishersci.com)
- PKC (Protein Kinase-C) is a cyclic nucleotide-independent enzyme that phosphorylates serine and threonine residues in many target proteins. (qiagen.com)
Human disorder1
- A definition of the term "ataxia telangiectasia," which is an autosomal recessive human disorder is presented. (ebscohost.com)
Regulation4
- The protein also functions in the regulation of the cell cycle in response to DNA damage. (genecards.org)
- a-synuclein may be involved in the regulation of dopamine release and transport and also may function to induce fibrillization of microtubule-associated protein tau. (biolegend.com)
- Xu P, LaVallee P, Lin J, Hoidal J. Characterization of proteins binding to E-box/Ku86 sites and function of Ku86 in transcriptional regulation of the human xanthine oxidoreductase gene. (labome.org)
- There are possible roles for both ions within the Golgi, including roles in protein modification, in regulation of sorting and vesicular traffic, and in removal of toxic levels of ions. (genetics.org)
Disorder2
- Ataxia-telangiectasia (A-T) is a rare degenerative disorder that first becomes apparent during childhood. (atcp.org)
- The ATM gene is mutated in the human genetic disorder ataxia telangiectasia ( 58 ). (asm.org)
Kinase activity4
- We determined that loss of TGFβ signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. (aacrjournals.org)
- It has been previously reported that herpes simplex virus type 1 (HSV-1) infection induces activation of protein kinase activity of ATM and hyperphosphorylation of transcription factor, Sp1. (pubfacts.com)
- Immunoprecipitated ATM had intrinsic protein kinase activity and phosphorylated p53 on serine-15 in a manganese-dependent manner. (sciencemag.org)
- Wild-type and mutant recombinant ATM proteins were individually expressed in 293T cells, and in vitro kinase activity was assessed ( 14 ). (sciencemag.org)
Phosphorylates2
- In the present study, we found that c-Abl phosphorylates JunB, a member of the AP-1 (activator protein 1) transcription factor family. (biochemj.org)
- The PI-3-K-related protein, DNA-activated protein kinase (DNA-PK) phosphorylates p53 in vitro at two different Ser-Gln motifs, Ser 15 and Ser 37 ( 9 ). (sciencemag.org)
Transcript1
- The most common form of the protein, is the full 140 amino acid-long transcript. (biolegend.com)