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CDK targeting of NBS1 promotes DNA-end resection, replication restart and homologous recombination

Jacob Falck1, Josep V Forment, Julia Coates

  • 1Department of Biochemistry, Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.

EMBO Reports
|May 9, 2012
PubMed

Insights

Cyclin-dependent kinase (CDK) phosphorylation of NBS1 protein is crucial for DNA double-strand break (DSB) repair via homologous recombination (HR). This modification also ensures DNA replication can resume after stalling.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • DNA Repair Mechanisms

Background:

  • The MRE11–RAD50–NBS1 (MRN) complex is essential for sensing DNA double-strand breaks (DSBs).
  • The MRN complex plays a key role in DNA repair pathways, including homologous recombination (HR) and end joining.

Purpose of the Study:

  • To identify NBS1 as a target of cyclin-dependent kinase (CDK) phosphorylation.
  • To elucidate the role of NBS1 phosphorylation in DNA double-strand break (DSB) repair and cell cycle progression.

Main Methods:

  • Investigated NBS1 phosphorylation sites and dependency on CDK activity.
  • Assessed the impact of impaired NBS1 phosphorylation on DSB repair by homologous recombination (HR).
  • Examined the effect of NBS1 phosphorylation on DNA replication recovery after fork stalling.

Main Results:

  • NBS1 is phosphorylated at serine 432 by CDKs during the S, G2, and M phases of the cell cycle.
  • NBS1 phosphorylation by CDKs promotes the conversion of DSBs into substrates for HR repair.
  • Disruption of NBS1 phosphorylation impairs DSB repair via HR and hinders DNA replication restart.

Conclusions:

  • CDK-mediated NBS1 phosphorylation acts as a molecular switch, directing the choice of DSB repair pathway.
  • This phosphorylation event is critical for both efficient DNA double-strand break repair and the restoration of DNA replication.

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