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

Nozomi Tomimatsu, Bipasha Mukherjee, Molly Catherine Hardebeck, Mariya Ilcheva, Cristel Vanessa Camacho, Janelle Louise Harris, Matthew Porteus, Bertrand Llorente, Kum Kum Khanna and Sandeep Burma ()
Additional contact information
Nozomi Tomimatsu: University of Texas Southwestern Medical Center
Bipasha Mukherjee: University of Texas Southwestern Medical Center
Molly Catherine Hardebeck: University of Texas Southwestern Medical Center
Mariya Ilcheva: University of Texas Southwestern Medical Center
Cristel Vanessa Camacho: University of Texas Southwestern Medical Center
Janelle Louise Harris: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute
Matthew Porteus: Deparment of Pediatrics, Stanford University
Bertrand Llorente: CRCM, Inserm, U1068; Aix-Marseille Université, UM 105; CNRS, UMR7258
Kum Kum Khanna: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute
Sandeep Burma: University of Texas Southwestern Medical Center

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/ncomms4561 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4561

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms4561

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().