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. Breast cancer: a critical switch Individuals with BRCA2 mutations are predisposed to breast cancers thought to develop due to defective repair of DNA double-strand breaks. BRCA2 protein is known to interact with the recombination protein RAD51, and a key step regulating this interaction has now been identified. Cdk1 alters the phosphorylation state of a single serine in BRCA2, and this acts a molecular switch controlling interactions between BRCA2's C-terminus and RAD51. Individuals carrying defects in the C-terminus of BRCA2 develop breast cancer through an inability to promote efficient DNA repair.