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Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair.

BRCA1 plays an important role in the homologous recombination (HR)-mediated DNA double-strand break (DSB) repair, but the mechanism is not clear. Here we describe that BRCA1 forms a complex with CtIP and MRN (Mre11/Rad50/Nbs1) in a cell cycle-dependent manner. Significantly, the complex formation, especially the ionizing radiation-enhanced association of BRCA1 with MRN, requires cyclin-dependent kinase activity. CtIP directly interacts with Nbs1. The in vivo association of BRCA1 with MRN is largely dependent on the association of CtIP with the BRCT domains at the C terminus of BRCA1, whereas the N terminus of BRCA1 also contributes to its association with MRN. CtIP, as well as the interaction of BRCA1 with CtIP and MRN, is critical for IR-induced single-stranded DNA formation and cellular resistance to radiation. Consistently, CtIP itself is required for efficient HR-mediated DSB repair, like BRCA1 and MRN. These studies suggest that the complex formation of BRCA1.CtIP.MRN is important for facilitating DSB resection to generate single-stranded DNA that is needed for HR-mediated DSB repair. Because cyclin-dependent kinase is important for establishing IR-enhanced interaction of MRN with BRCA1, we propose that the cell cycle-dependent complex formation of BRCA1, CtIP, and MRN contributes to the activation of HR-mediated DSB repair in the S and G(2) phases of the cell cycle.

Pubmed ID: 18171670

Authors

  • Chen L
  • Nievera CJ
  • Lee AY
  • Wu X

Journal

The Journal of biological chemistry

Publication Data

March 21, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA102361

Mesh Terms

  • BRCA1 Protein
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Line
  • Cyclin-Dependent Kinases
  • DNA Breaks, Double-Stranded
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • G2 Phase
  • Humans
  • Multiprotein Complexes
  • Nuclear Proteins
  • Protein Structure, Tertiary
  • Radiation, Ionizing
  • S Phase