hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response

Mutations in the BRCA1 (ref. 1) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer(2,3). Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair(4-7) and cell-cycle checkpoints(8-10). BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage(11,12). It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related. In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family(13-20). Here we report that the human Cds1 kinase (hCds1/Chk2)(21-23) regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and colocalize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937.