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

Nozomi Tomimatsu1, Bipasha Mukherjee1, Molly Catherine Hardebeck1

  • 1Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 2201 Inwood Road, NC7, 214E, Dallas, Texas 75390, USA.

Nature Communications
|April 8, 2014
PubMed

Insights

Cyclin-dependent kinases (CDKs) regulate DNA repair pathway choice by phosphorylating the EXO1 nuclease. This phosphorylation is crucial for DNA double-strand break resection, chromosomal integrity, and favoring homologous recombination over NHEJ.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA double-strand breaks (DSBs) are repaired via Non-Homologous End Joining (NHEJ) or Homologous Recombination (HR).
  • Cyclin-dependent kinases (CDKs) initiate DNA repair resection, but their role in long-range resection is unclear.

Purpose of the Study:

  • To investigate the role of CDKs in regulating long-range resection of DNA double-strand breaks.
  • To elucidate the mechanism by which CDKs influence DNA repair pathway choice.

Main Methods:

  • Investigated CDK-mediated phosphorylation of the EXO1 nuclease at C-terminal S/TP sites.
  • Utilized phospho-mimic and phospho-deficient EXO1 mutations in cell-based assays.
  • Assessed resection, chromosomal integrity, cell survival, and DNA repair pathway choice (HR vs. NHEJ).

Main Results:

  • CDKs 1/2 phosphorylate EXO1 during S/G2 phases, promoting long-range resection.
  • Impaired EXO1 phosphorylation reduces resection, chromosomal integrity, and HR, while increasing NHEJ.
  • Phospho-mimic EXO1 rescues resection and favors HR even with CDK inhibition.

Conclusions:

  • CDK-mediated phosphorylation of EXO1 is a novel regulatory mechanism for DNA double-strand break repair pathway choice.
  • Phosphorylation enhances EXO1 recruitment to DNA breaks, potentially through BRCA1 interaction.
  • This mechanism is critical for maintaining genomic stability and directing repair towards HR.

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