title: The K898E germline variant in the PP1-binding motif of BRCA1 causes defects in DNA Repair.
abstract: BRCA1 is a phosphoprotein involved in many biological processes, including transcription, ubiquitination, checkpoint control, homologous recombination, and DNA repair. We have demonstrated that protein phosphatase 1α (PP1α) interacts with BRCA1 via a PP1-binding motif (898)KVTF(901), and can dephosphorylate multiple serine residues phosphorylated by checkpoint kinases. A K898E germline missense variant in the PP1-binding motif of BRCA1 has been found in an Ashkenazi patient and a non-Ashkenazi Argentinean patient with breast and ovarian cancer, but its clinical significance is still unknown. Here we report that the lysine residue in the PP1-binding motif of BRCA1 is highly conserved across many mammalian species. The K898E mutation interferes with the interaction between BRCA1 and PP1α. Moreover, while the expression of wild-type BRCA1 in Brca1-deficient cells improved cell survival after DNA damage induced by ionizing radiation (IR), expression of BRCA1 K898E proved unable to enhance cell survival. DNA damage repair mechanisms remained defective in these BRCA1 K898E-reconstituted cells, as revealed by the comet assay and IR-induced Rad51 foci formation assay. These results reflect the significance of the interaction between BRCA1 and PP1, and indicate that the K898E variant may render carriers susceptible to DNA damage and malignant transformation.
authors: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan, ROC.
authors: Bert Yu-Hung
authors: BY
authors: Chen
authors: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan, ROC.
authors: Cheng-Hsiang
authors: CH
authors: Huang
authors: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan, ROC.
authors: Ying-Hsi
authors: YH
authors: Lin
authors: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan, ROC.
authors: Ching-Chun
authors: CC
authors: Huang
authors: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Chu-Xia
authors: CX
authors: Deng
authors: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan, ROC.
authors: Lih-Ching
authors: LC
authors: Hsu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics*; D001665:Binding Sites; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D004260:DNA Repair; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D051135:Rad51 Recombinase / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase