Abstract A10: The impact of cancer-associated RAD51C mutations in homologous recombination

Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks (DSBs). Loss of function of key HR repair proteins have been linked to diseases characterized by genomic instability including cancers and Fanconi anemia. Regulation of RAD51 filaments is critical during HR repair and is mediated by several factors including the RAD51 paralogs, a group of proteins that share sequence homology with RAD51. The RAD51 paralog family consists of five proteins in humans, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. The RAD51 paralog, RAD51C, has recently become a key protein of interest as RAD51C mutations have been linked to familial breast and ovarian cancers. However, the specific functions of RAD51C have remained enigmatic as mouse and non-tumorigenic knockout models are inviable. Given these limitations, we have identified RAD51C point mutations from breast and ovarian cancer patients to study the phenotypes of these RAD51C mutants and how they impair homologous recombination. We have found that RAD51C mutations can disrupt interactions with RAD51 paralog binding partners, RAD51B and XRCC3, required for RAD51C stability. Through yeast-two/three-hybrid and co-immunoprecipitation experiments, we isolated RAD51C mutations that disrupt interactions within RAD51 paralog complexes. These complexes have important roles in the repair of classical DSBs induced by ionizing radiation or chemotherapeutic reagents as well as in replication fork protection such as after...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Homologous Recombination Defects: Poster Presentations - Proffered Abstracts Source Type: research