Abstract A27: Assessing somatic tumor-associated RAD51 mutations and screening for novel dominant-interfering RAD51 proteins

The responsiveness of cancer cells to chemotherapy and targeted treatment, as well as the development of resistance, is determined by the state of DNA damage response pathways. Homology-directed repair (HDR) is crucial for error-free repair of DNA double-strand breaks that arise during replication stress or are induced by exogenous genotoxins. Therefore, HDR efficacy status in cancer cells could potentially be utilized as an indicator to predict tumor responsiveness to standard chemotherapies and to poly(ADP-ribose) polymerases (PARP) inhibitors. We are interested in understanding the influence of different levels of functional activity of the HDR pathway on treatment responses.To this end, we have investigated the functional consequence of RAD51 point mutations identified in tumors. RAD51 is an effector of the key tumor suppressor BRCA2 and contributes to genome integrity in actively dividing cells. RAD51 mutations are identified from Memorial Sloan Kettering clinical sequencing cohort (MSK-IMPACT), the Catalogue of Somatic Mutations in Cancer (COSMIC) and the International Fanconi Anemia Registry (IFAR). To understand the implications of these altered residues on RAD51 function in HDR, we tested repair efficiency using a previously established DR-GFP reporter assay in mammalian cells. Of eighteen novel RAD51 mutants examined, ten displayed decreased HDR efficiency, three had wild-type levels of HDR, and five had increased HDR levels. To test whether the HDR-deficient RAD51 ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: DNA Repair Gene Mutations in Cancer Genomes: Poster Presentations - Proffered Abstracts Source Type: research