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 K.um Khanna, Sandeep Burma

Research output: Contribution to journalArticle

90 Scopus citations

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.

Original languageEnglish (US)
Article number3561
Number of pages1
JournalNature communications
Volume5
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Tomimatsu, N., Mukherjee, B., Catherine Hardebeck, M., Ilcheva, M., Vanessa Camacho, C., Louise Harris, J., Porteus, M., Llorente, B., Khanna, K. K. U., & Burma, S. (2014). Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nature communications, 5, [3561]. https://doi.org/10.1038/ncomms4561