A Pathway of Double-Strand Break Rejoining Dependent upon ATM, Artemis, and Proteins Locating to γ-H2AX Foci

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 i...

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Bibliographic Details
Published in:Molecular cell 2004-12, Vol.16 (5), p.715-724
Main Authors: Riballo, Enriqueta, Kühne, Martin, Rief, Nicole, Doherty, Aidan, Smith, Graeme C.M., Recio, Marı́a-José, Reis, Caroline, Dahm, Kirsten, Fricke, Andreas, Krempler, Andrea, Parker, Antony R., Jackson, Stephen P., Gennery, Andrew, Jeggo, Penny A., Löbrich, Markus
Format: Article
Language:English
Subjects:
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
Mice
MRE11 Homologue Protein
Nuclear Proteins - metabolism
Nuclear Proteins - physiology
Phenotype
Phosphoproteins - metabolism
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Severe Combined Immunodeficiency
Signal Transduction
Time Factors
Tumor Suppressor p53-Binding Protein 1
Tumor Suppressor Proteins
X-Rays
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Summary: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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2004.10.029