CDK-dependent Phosphorylation of BRCA2 as a Regulatory Mechanism for Recombinational Repair

Nature. 2005 Mar 31;434(7033):598-604. doi: 10.1038/nature03404.

Abstract

Inherited mutations in BRCA2 are associated with a predisposition to early-onset breast cancers. The underlying basis of tumorigenesis is thought to be linked to defects in DNA double-strand break repair by homologous recombination. Here we show that the carboxy-terminal region of BRCA2, which interacts directly with the essential recombination protein RAD51, contains a site (serine 3291; S3291) that is phosphorylated by cyclin-dependent kinases. Phosphorylation of S3291 is low in S phase when recombination is active, but increases as cells progress towards mitosis. This modification blocks C-terminal interactions between BRCA2 and RAD51. However, DNA damage overcomes cell cycle regulation by decreasing S3291 phosphorylation and stimulating interactions with RAD51. These results indicate that S3291 phosphorylation might provide a molecular switch to regulate RAD51 recombination activity, providing new insight into why BRCA2 C-terminal deletions lead to radiation sensitivity and cancer predisposition.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • BRCA2 Protein / chemistry
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line
  • Cyclin-Dependent Kinases / metabolism*
  • DNA Damage / genetics
  • DNA Repair / genetics*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Molecular Sequence Data
  • Nuclear Localization Signals
  • Phosphorylation
  • Protein Binding
  • Rad51 Recombinase
  • Recombination, Genetic / genetics*
  • Sequence Deletion / genetics

Substances

  • BRCA2 Protein
  • DNA-Binding Proteins
  • Nuclear Localization Signals
  • Cyclin-Dependent Kinases
  • RAD51 protein, human
  • Rad51 Recombinase