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J Cell Biol. September 5, 2011; 194 (5): 705-20.

Cdk1 uncouples CtIP-dependent resection and Rad51 filament formation during M-phase double-strand break repair.

Peterson SE , Li Y , Chait BT , Gottesman ME , Baer R , Gautier J .

DNA double-strand break (DSB) resection, which results in RPA-bound single-stranded DNA (ssDNA), is activated in S phase by Cdk2. RPA-ssDNA activates the ATR-dependent checkpoint and homology-directed repair (HDR) via Rad51-dependent mechanisms. On the other hand, the fate of DSBs sustained during vertebrate M phase is largely unknown. We use cell-free Xenopus laevis egg extracts to examine the recruitment of proteins to chromatin after DSB formation. We find that S-phase extract recapitulates a two-step resection mechanism. M-phase chromosomes are also resected in cell-free extracts and cultured human cells. In contrast to the events in S phase, M-phase resection is solely dependent on MRN-CtIP. Despite generation of RPA-ssDNA, M-phase resection does not lead to ATR activation or Rad51 chromatin association. Remarkably, we find that Cdk1 permits resection by phosphorylation of CtIP but also prevents Rad51 binding to the resected ends. We have thus identified Cdk1 as a critical regulator of DSB repair in M phase. Cdk1 induces persistent ssDNA-RPA overhangs in M phase, thereby preventing both classical NHEJ and Rad51-dependent HDR.

PubMed ID: 21893598
PMC ID: PMC3171114
Article link: J Cell Biol.
Grant support: R01CA092245 NCI NIH HHS , R01GM077495 NIGMS NIH HHS , RR00862 NCRR NIH HHS , RR022220 NCRR NIH HHS , P01 CA097403 NCI NIH HHS , R01 GM077495 NIGMS NIH HHS , R01 CA092245 NCI NIH HHS , P41 RR000862 NCRR NIH HHS , U54 RR022220 NCRR NIH HHS

Genes referenced: atr cdk1 cdk2 chek1 dna2 exo1 gmnn mre11 rad51 rbbp8 rpa1

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Anantha, 2008, Pubmed[+]

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