Abstract 620: Defects of homologous recombination repair in breast cancer: Identification of a novel RAD51-associated protein complex.

Abstract

Abstract Cells are continuously challenged by genotoxic agents from endogenous and exogenous sources. Severe DNA lesions, including DNA double-strand breaks (DSBs), have to be appropriately repaired for cell survival. Homologous recombination (HR) is particularly important for the repair of DSBs due to its ability to accurately restore genetic information. “Cancer is a disease of DNA repair”. The breast cancer susceptibility genes BRCA1 and BRCA2 encode DNA repair factors acting in the specific HR repair pathway. Germline mutations in many HR components, including BRCA1, BRCA2 and PALB2, are associated with cancers including breast cancer. Therefore, it is urgent to understand how HR repair is regulated in normal cells and how human cancers are defective in HR mediated repair. The RAD51 recombinase plays a central role in HR. To further study HR process, we performed tandem affinity purification of RAD51. Here, we report the identification of a new RAD51-binding protein FIGNL1 (fidgetin-like 1). Our experiments showed that FIGNL1 specifically interacts with RAD51 via its conserved RAD51-binding domain. Cells depleted of FIGNL1 show defective HR repair and hypersensitivity to Camptothecin and ionizing radiation, common regimens for cancer treatment. However, FIGNL1 is recruited to sites of DNA damage in a manner that is independent of BRCA2, RAD51 and RAD51 paralogs. Conversely, FIGNL1 depletion does not affect the loading of RAD51 onto single-strand DNA. Our experiments also uncovered KIAA0146 as a binding partner of FIGNL1 and established that KIAA0146 acts together with FIGNL1 in HR repair. More interestingly, our further study revealed that FIGNL1 and KIAA0146 protein level is dramatically reduced in some breast cancer cell lines. Altogether, our study reveals a sub-pathway of HR repair with newly identified components FIGNL1 and KIAA0146 and suggests their possible defects in breast cancer, therefore provides new potential directions for cancer diagnosis and therapy. Citation Format: Jingsong Yuan, Junjie Chen. Defects of homologous recombination repair in breast cancer: Identification of a novel RAD51-associated protein complex. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 620. doi:10.1158/1538-7445.AM2013-620