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Nat Commun. 2014 Apr 7;5:3561. doi: 10.1038/ncomms4561.

Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice.

Author information

1
Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Road, NC7, 214E, Dallas, Texas 75390, USA.
2
1] Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Road, NC7, 214E, Dallas, Texas 75390, USA [2].
3
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
4
Deparment of Pediatrics, Stanford University, Stanford, California 94395, USA.
5
CRCM, Inserm, U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM 105; CNRS, UMR7258, Marseille F-13009, France.

Abstract

Resection of DNA double-strand breaks (DSBs) is a pivotal step during which the choice between NHEJ and HR DNA repair pathways is made. Although CDKs are known to control initiation of resection, their role in regulating long-range resection remains elusive. Here we show that CDKs 1/2 phosphorylate the long-range resection nuclease EXO1 at four C-terminal S/TP sites during S/G2 phases of the cell cycle. Impairment of EXO1 phosphorylation attenuates resection, chromosomal integrity, cell survival and HR, but augments NHEJ upon DNA damage. In contrast, cells expressing phospho-mimic EXO1 are proficient in resection even after CDK inhibition and favour HR over NHEJ. Mutation of cyclin-binding sites on EXO1 attenuates CDK binding and EXO1 phosphorylation, causing a resection defect that can be rescued by phospho-mimic mutations. Mechanistically, phosphorylation of EXO1 augments its recruitment to DNA breaks possibly via interactions with BRCA1. In summary, phosphorylation of EXO1 by CDKs is a novel mechanism regulating repair pathway choice.

PMID:
24705021
PMCID:
PMC4041212
DOI:
10.1038/ncomms4561
[Indexed for MEDLINE]
Free PMC Article

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