Mre11 regulates CtIP-dependent double-strand break repair by interaction with CDK2.
Homologous recombination facilitates accurate repair of DNA double-strand breaks (DSBs) during the S and G2 phases of the cell cycle by using intact sister chromatids as sequence templates. Homologous recombination capacity is maximized in S and G2 by cyclin-dependent kinase (CDK) phosphorylation of CtIP, which subsequently interacts with BRCA1 and the Mre11-Rad50-NBS1 (MRN) complex. Here we show that, in human and mouse, Mre11 controls these events through a direct interaction with CDK2 that is required for CtIP phosphorylation and BRCA1 interaction in normally dividing cells. CDK2 binds the C terminus of Mre11, which is absent in an inherited allele causing ataxia telangiectasia-like disorder. This newly uncovered role for Mre11 does not require ATM activation or nuclease activities. Therefore, functions of MRN are not restricted to DNA damage responses but include regulating homologous recombination capacity during the normal mammalian cell cycle.
Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
Jeffrey
J
Buis
Trina
T
Stoneham
Elizabeth
E
Spehalski
David O
DO
Ferguson
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004706:Endodeoxyribonucleases; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011995:Recombination, Genetic
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D051357:Cyclin-Dependent Kinase 2; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins; C501070:RBBP8 protein, mouse; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; C410741:RBBP8 protein, human