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- Title
CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair.
- Authors
Esashi, Fumiko; Christ, Nicole; Gannon, Julian; Liu, Yilun; Hunt, Tim; Jasin, Maria; West, Stephen C
- 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
Nature, 2005, Vol 434, Issue 7033, p598
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature03404