1. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci.
- Author
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Riballo E, Kühne M, Rief N, Doherty A, Smith GC, Recio MJ, Reis C, Dahm K, Fricke A, Krempler A, Parker AR, Jackson SP, Gennery A, Jeggo PA, and Löbrich M
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins metabolism, Cell Line, Cells, Cultured, DNA Repair, DNA Repair Enzymes, DNA, Complementary metabolism, DNA-Binding Proteins metabolism, Dose-Response Relationship, Radiation, Endonucleases, Epistasis, Genetic, Gamma Rays, Genetic Complementation Test, Humans, Infrared Rays, Intracellular Signaling Peptides and Proteins metabolism, MRE11 Homologue Protein, Mice, Nuclear Proteins metabolism, Phenotype, Phosphoproteins metabolism, Phosphorylation, Severe Combined Immunodeficiency, Signal Transduction, Time Factors, Tumor Suppressor Proteins, Tumor Suppressor p53-Binding Protein 1, X-Rays, DNA Damage, Histones metabolism, Nuclear Proteins physiology, Protein Serine-Threonine Kinases metabolism
- Abstract
The hereditary disorder ataxia telangiectasia (A-T) is associated with striking cellular radiosensitivity that cannot be attributed to the characterized cell cycle checkpoint defects. By epistasis analysis, we show that ataxia telangiectasia mutated protein (ATM) and Artemis, the protein defective in patients with RS-SCID, function in a common double-strand break (DSB) repair pathway that also requires H2AX, 53BP1, Nbs1, Mre11, and DNA-PK. We show that radiation-induced Artemis hyperphosphorylation is ATM dependent. The DSB repair process requires Artemis nuclease activity and rejoins approximately 10% of radiation-induced DSBs. Our findings are consistent with a model in which ATM is required for Artemis-dependent processing of double-stranded ends with damaged termini. We demonstrate that Artemis is a downstream component of the ATM signaling pathway required uniquely for the DSB repair function but dispensable for ATM-dependent cell cycle checkpoint arrest. The significant radiosensitivity of Artemis-deficient cells demonstrates the importance of this component of DSB repair to survival.
- Published
- 2004
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