title: 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.affiliation: Genome Damage and Stability Centre, University of Sussex, East Sussex, BN1 9RQ, United Kingdom.
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Riballo
authors.forename: Martin
authors.initials: M
authors.lastname: Kühne
authors.forename: Nicole
authors.initials: N
authors.lastname: Rief
authors.forename: Aidan
authors.initials: A
authors.lastname: Doherty
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: María-José
authors.initials: MJ
authors.lastname: Recio
authors.forename: Caroline
authors.initials: C
authors.lastname: Reis
authors.forename: Kirsten
authors.initials: K
authors.lastname: Dahm
authors.forename: Andreas
authors.initials: A
authors.lastname: Fricke
authors.forename: Andrea
authors.initials: A
authors.lastname: Krempler
authors.forename: Antony R
authors.initials: AR
authors.lastname: Parker
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.forename: Andrew
authors.initials: A
authors.lastname: Gennery
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
authors.forename: Markus
authors.initials: M
authors.lastname: Löbrich
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004720:Endonucleases; D004843:Epistasis, Genetic; D005720:Gamma Rays; D005816:Genetic Complementation Test; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007259:Infrared Rays; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000076228:MRE11 Homologue Protein; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016511:Severe Combined Immunodeficiency; D015398:Signal Transduction; D013997:Time Factors; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D014965:X-Rays
chemical_list: D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006657:Histones; C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; C112156:NBN protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; C498301:TP53BP1 protein, human; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C475961:gamma-H2AX protein, mouse; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C426344:DCLRE1C protein, human; D004720:Endonucleases; D000076228:MRE11 Homologue Protein; C473337:Dclre1c protein, mouse; D045643:DNA Repair Enzymes