A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci.

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.
Authors	Enriqueta Riballo, Martin Kühne, Nicole Rief, Aidan Doherty, Graeme C M Smith, María-José Recio, Caroline Reis, Kirsten Dahm, Andreas Fricke, Andrea Krempler, Antony R Parker, Stephen P Jackson, Andrew Gennery, Penny A Jeggo, Markus Löbrich
Journal	Molecular cell (Mol Cell) Vol. 16 Issue 5 Pg. 715-24 (Dec 03 2004) ISSN: 1097-2765 [Print] United States
PMID	15574327 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cell Cycle Proteins DNA, Complementary DNA-Binding Proteins Histones Ifi202b protein, mouse Intracellular Signaling Peptides and Proteins MRE11 protein, human Mre11a protein, mouse NBN protein, human Nuclear Proteins Phosphoproteins TP53BP1 protein, human Tumor Suppressor Proteins Tumor Suppressor p53-Binding Protein 1 gamma-H2AX protein, mouse ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases DCLRE1C protein, human Endonucleases MRE11 Homologue Protein Dclre1c protein, mouse DNA Repair Enzymes
Topics	Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins (metabolism) Cell Line Cells, Cultured DNA Damage DNA Repair DNA Repair Enzymes DNA, Complementary (metabolism) DNA-Binding Proteins (metabolism) Dose-Response Relationship, Radiation Endonucleases Epistasis, Genetic Gamma Rays Genetic Complementation Test Histones (metabolism) Humans Infrared Rays Intracellular Signaling Peptides and Proteins (metabolism) MRE11 Homologue Protein Mice Nuclear Proteins (metabolism, physiology) Phenotype Phosphoproteins (metabolism) Phosphorylation Protein Serine-Threonine Kinases (metabolism) Severe Combined Immunodeficiency Signal Transduction Time Factors Tumor Suppressor Proteins Tumor Suppressor p53-Binding Protein 1 X-Rays

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