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CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair.

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.

Pubmed ID: 15800615


  • Esashi F
  • Christ N
  • Gannon J
  • Liu Y
  • Hunt T
  • Jasin M
  • West SC



Publication Data

March 31, 2005

Associated Grants

  • Agency: Wellcome Trust, Id: 101009

Mesh Terms

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