title: Human CtIP mediates cell cycle control of DNA end resection and double strand break repair.
abstract: In G(0) and G(1), DNA double strand breaks are repaired by nonhomologous end joining, whereas in S and G(2), they are also repaired by homologous recombination. The human CtIP protein controls double strand break (DSB) resection, an event that occurs effectively only in S/G(2) and that promotes homologous recombination but not non-homologous end joining. Here, we mutate a highly conserved cyclin-dependent kinase (CDK) target motif in CtIP and reveal that mutating Thr-847 to Ala impairs resection, whereas mutating it to Glu to mimic constitutive phosphorylation does not. Moreover, we show that unlike cells expressing wild-type CtIP, cells expressing the Thr-to-Glu mutant resect DSBs even after CDK inhibition. Finally, we establish that Thr-847 mutations to either Ala or Glu affect DSB repair efficiency, cause hypersensitivity toward DSB-generating agents, and affect the frequency and nature of radiation-induced chromosomal rearrangements. These results suggest that CDK-mediated control of resection in human cells operates by mechanisms similar to those recently established in yeast.
authors.affiliation: Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge CB2 1QN, United Kingdom.
authors.forename: Pablo
authors.initials: P
authors.lastname: Huertas
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004706:Endodeoxyribonucleases; D042822:Genomic Instability; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016415:Sequence Alignment
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D004247:DNA; D018844:Cyclin-Dependent Kinases; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human