title: ATM-dependent phosphorylation of the checkpoint clamp regulates repair pathways and maintains genomic stability.
abstract: Upon genotoxic stress and during normal S phase, ATM phosphorylates the checkpoint clamp protein Rad9 in a manner that depends on Ser272. Ser272 is the only known ATM-dependent phosphorylation site in human Rad9. However, Ser272 phosphorylation is not required for survival or checkpoint activation after DNA damage. The physiological function of Ser272 remains elusive. Here, we show that ATM-dependent Rad9(Ser272) phosphorylation requires the MRN complex and controls repair pathways. Furthermore, the mutant cells accumulate large numbers of chromosome breaks and induce gross chromosomal rearrangements. Our findings establish a new and unexpected role for ATM: it phosphorylates the checkpoint clamp in order to control repair pathways, thereby maintaining genomic integrity during unperturbed cell cycle and upon DNA damage.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Min Hwa
authors.initials: MH
authors.lastname: Shin
authors.forename: Ming
authors.initials: M
authors.lastname: Yuan
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Margolick
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kai
mesh_terms: D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019457:Chromosome Breakage; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D000076228:MRE11 Homologue Protein; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D059767:Recombinational DNA Repair; D012694:Serine / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D009025:Morpholines; D046912:Multiprotein Complexes; C112156:NBN protein, human; D009687:Nuclear Proteins; D011753:Pyrones; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C069930:rad9 protein; D012694:Serine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes