Abstract AP05: OVARIAN CANCER-ASSOCIATED RAD51D MUTATIONS WHICH IMPAIR ITS INTERACTION WITH XRCC2 RESULT IN DNA REPAIR DEFICIENCY

Abstract

The proficiency of ovarian cancer cells to repair DNA double-strand breaks (DSBs) by homologous recombination (HR) is a key determinant in predicting response to targeted therapies such as PARP inhibitors (PARPi). The RAD51 paralogs act downstream of BRCA1/2 to facilitate HR. Numerous epidemiological studies have linked mutations in the RAD51 paralogs with hereditary ovarian cancer predisposition. Despite their substantial links to cancer predisposition and development, RAD51 paralog function during HR has remained elusive, in part due to limitations in studying recombination events downstream of RAD51 filament formation. Here we investigate the impact of cancer-associated mutations in the RAD51 paralog, RAD51D, using yeast 2/3-hybrid assays to screen for altered protein-protein interactions. Following the identification of mutations that disrupt the interaction between RAD51D and XRCC2 in yeast, we validated the interaction by co-immunoprecipitation in human cells. Importantly, we determined the impact of these mutations on HR-proficiency using a direct-repeat recombination assay. By characterizing the impact of cancer-associated mutations in the RAD51 paralogs on HR-proficiency, we aim to develop more effective predictive models for therapeutic sensitivity and resistance in patients who harbor similar mutations in these essential genes. Citation Format: Robert A. Baldock, Catherine A. Pressimone, Jared M. Baird, Anton Y. Khodakov, Yoav Karpenshif, Edwige B. Garcin, Stéphanie Gon, Mauro Modesti, Kara A. Bernstein. OVARIAN CANCER-ASSOCIATED RAD51D MUTATIONS WHICH IMPAIR ITS INTERACTION WITH XRCC2 RESULT IN DNA REPAIR DEFICIENCY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP05.