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Breast cancer is one of the most common malignancies affecting women worldwide. Individuals with a mutation in the breast cancer associated gene-1 (BRCA1) are at a higher risk of developing breast cancer. Finding new genes that function in BRCA1 controlled pathways might help in understanding the pathogenesis of the disease and in discovering new genes that might contribute to the development of breast cancer and that might ultimately serve as new therapeutic targets. The majority of the BRCA1 mutations presented clinically are non-sense mutations that form a truncated non-functional protein. About 36% of the BRCA1 mutations however, are missense mutations with a single amino acid change. The impact of most of these mutations on the BRCA1 function is still unknown and therefore, their contribution to the development of the disease is yet to be determined. BRCA1 is a protein that functions in multiple pathways including DNA repair and control of centrosome number. Determining the impact of BRCA1 missense mutations on the function of the protein and finding new BRCA1 interactors that function in BRCA1 controlled pathways is important for the discovery of pathogenic BRCA1 mutants and new potential biomarkers for breast cancers that might contribute to the pathogenesis of the disease. In this study, we assess the impact of 14 missense mutations in the ring domain of the BRCA1 gene on the control of the centrosomes, and we compare our results to results from another assay performed in our laboratory looking at the effect of the same mutations on homologous recombination. In addition, and using a bioinformatics approach, we identify a new BRCA1 interactor: KIAA0101 (PAF15) and we assess the function of this protein in several BRCA1 controlled pathways. Our studies classified the tested BRCA1 mutants as being neutral or pathogenic in the control of centrosome numbers which is a critical step in the maintenance of genomic stability of mammary epithelial cells. In addition, the informatics analysis identified a new BRCA1 interactor which we revealed its function in the control of centrosome duplication and its involvement in the UV-induced damage response, a pathway also controlled by BRCA1. In conclusion, our experimental framework has developed new tools to identify new candidate genes whose regulation suggests potential involvement in breast carcinogenesis, and to identify pathogenic BRCA1 mutations that might contribute to the development of the breast cancer. |
