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 RIS Download
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