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

EMBO Rep. 2012 Jun;13(6):561-8. doi: 10.1038/embor.2012.58.

Abstract

The conserved MRE11–RAD50–NBS1 (MRN) complex is an important sensor of DNA double-strand breaks (DSBs) and facilitates DNA repair by homologous recombination (HR) and end joining. Here, we identify NBS1 as a target of cyclin-dependent kinase (CDK) phosphorylation. We show that NBS1 serine 432 phosphorylation occurs in the S, G2 and M phases of the cell cycle and requires CDK activity. This modification stimulates MRN-dependent conversion of DSBs into structures that are substrates for repair by HR. Impairment of NBS1 phosphorylation not only negatively affects DSB repair by HR, but also prevents resumption of DNA replication after replication-fork stalling. Thus, CDK-mediated NBS1 phosphorylation defines a molecular switch that controls the choice of repair mode for DSBs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases
  • Amino Acid Substitution
  • CDC2 Protein Kinase / chemistry
  • CDC2 Protein Kinase / metabolism*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • DNA Cleavage*
  • DNA Repair
  • DNA Repair Enzymes / chemistry
  • DNA Replication*
  • DNA-Binding Proteins / chemistry
  • Homologous Recombination*
  • Humans
  • MRE11 Homologue Protein
  • Mutagenesis, Site-Directed
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Serine / genetics
  • Serine / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • NBN protein, human
  • Nuclear Proteins
  • Serine
  • CDC2 Protein Kinase
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, human
  • DNA Repair Enzymes