title: hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response.
abstract: 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. Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair and cell-cycle checkpoint. BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage. 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. Here we report that the human Cds1 kinase (hCds1/Chk2) regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and co-localize 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.
authors.affiliation: Laboratory of Molecular Hematology, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.forename: K M
authors.initials: KM
authors.lastname: Collins
authors.forename: A L
authors.initials: AL
authors.lastname: Brown
authors.forename: C H
authors.initials: CH
authors.lastname: Lee
authors.forename: J H
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D005720:Gamma Rays; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding / Q000528:radiation effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D011993:Recombinant Fusion Proteins; D012694:Serine; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases