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

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.

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Figure 1: Phosphorylation of the C-terminal RAD51-interaction domain of BRCA2.
Figure 2: S3291 phosphorylation blocks interactions between the C terminus of BRCA2 and RAD51.
Figure 3: Analysis of the phosphorylation status of S3291 in vivo.
Figure 4: Involvement of S3291 phosphorylation in mediating RAD51 interactions and efficient homologous recombination.

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Acknowledgements

We thank A. Venkitaraman for providing GST–B2-1 to B2-9. F.E. and N.C are recipients of postdoctoral fellowships from the Human Frontier Scientific Program, and Y.L. is a fellow of the American Cancer Society. This work was supported by Cancer Research UK, the Swiss Bridge Fund and the Breast Cancer Campaign (S.C.W.), and by the Emerald Foundation and an NIH grant (M.J.).

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Correspondence to Stephen C. West.

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Esashi, F., Christ, N., Gannon, J. et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434, 598–604 (2005). https://doi.org/10.1038/nature03404

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