ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2008; 4(6):352-361. doi:10.7150/ijbs.4.352 This issue Cite
Research Paper
A PP1-binding motif present in BRCA1 plays a role in its DNA repair function
1. Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Pittsburgh, Magee-Womens Research Institute, Pittsburgh, PA15213, USA
2. Genetics of Development and Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
3. School of Pharmacy, National Taiwan University College of Medicine, Taipei 10051, Taiwan, ROC
Abstract
Protein phosphatase 1α (PP1α) regulates phosphorylation of BRCA1, which contains a PP1-binding motif 898KVTF901. Mutation of this motif greatly reduces the interaction between BRCA1 and PP1α. Here we show that mutation of the PP1-binding motif abolishes the ability of BRCA1 to enhance survival of Brca1-deficient mouse mammary tumor cells after DNA damage. The Rad51 focus formation and comet assays revealed that the DNA repair function of BRCA1 was impaired when the PP1-binding motif was mutated. Analysis of subnuclear localization of GFP-tagged BRCA1 demonstrated that mutation of the PP1-binding motif affected BRCA1 redistribution in response to DNA damage. BRCA1 is required for the formation of Rad51 subnuclear foci after DNA damage. Mutation of the PP1-binding motif in BRCA1 also affected recruitment of Rad51 to sites of DNA damage. Consistent with these findings, knockdown of PP1α in BRCA1-proficient cells by small interfering RNA also significantly reduced Rad51 focus formation induced by DNA damage. Further analysis indicated that mutation of the PP1-binding motif compromised BRCA1 activities in homologous recombination. Altogether, our data implicate that interaction with PP1α is important for BRCA1 function in DNA repair.
Keywords: BRCA1, protein phosphatase 1, DNA repair
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