"Biochemical and functional analysis of DNA repair genes linked to breast and ovarian cancer development"
This seminar will describe new studies from the Bernstein lab, which functionally characterize every potential mutation in the tumor suppressor RAD51D (nearly 7000 mutations) using state-of-the-art deep mutational scanning combined with biochemical analysis of the most important functional regions.
Breast and ovarian cancers can be caused by a combination of our environmental exposures as well as our genetic make-up. Family history of cancer can be used to predict whether individuals need additional screening or testing. We know that inactivation of some genes leads to a higher risk of breast cancer. Our lab has been focusing on other genes that lead to increased breast/ovarian cancer risk, including the DNA repair gene, RAD51D. RAD51D contains ATPase domains and binds DNA. Mutations in RAD51D have been observed in high grade serous ovarian cancers and triple-negative breast cancers, which are typically very aggressive and difficult to treat.
Using a cutting-edge deep mutational scanning approach, we investigated the function of every coding variant of RAD51D. The resulting variant-to-function map successfully distinguishes between known cancer-causing and benign variants. This finding is validated by additional DNA repair and biochemical assays performed on 70 cancer-identified variants. Our analysis reveals that variants affecting the DNA-binding or ATPase core significantly impair DNA repair. We also identify the interface between RAD51D and its binding partner RAD51C as crucial for regulating ATPase activity. In summary, we pinpoint hotspots of harmful RAD51D variants and uncover the mechanisms by which these variants compromise its biochemical functions.