Abstract 1751: The role of SIRT2 in BRCA1 regulation

Abstract

Abstract The most deleterious type of DNA damage a cell can sustain is the DNA double-stranded break (DSB). One of the major pathways responsible for the repair of DNA DSB breaks is the homologous recombination (HR) pathway, an error-free mechanism of repair that occurs primarily in the S and G2 phases of the cell cycle when a sister chromatid is available to be used as a repair template. Impairment of HR can result in genomic instability, which can increase the risk of tumorigenesis. However, many of the mechanisms by which defects in HR lead to an increased risk for developing cancer are unknown. Mutations or misregulation of the Breast Cancer 1 (BRCA1) protein, a major player in HR and an established tumor suppressor, have been linked to an increased lifetime risk for the development of cancer in both men and women, including colon, breast, ovarian, and pancreatic cancer. Yet, how BRCA1 is regulated in HR is not well understood and thus highlights a major a gap in our understanding of how deficiencies in HR contribute to the development of cancer. Our lab has discovered that the histone deacetylase and putative human tumor suppressor, SIRT2, has a crucial role in the repair of DNA DSBs. We have found that SIRT2 interacts with and deacetylates BRCA1, both in vitro and in cells, and that depletion of SIRT2 decreases BRCA1 protein levels, thus impairing HR. Our results show SIRT2 is a novel regulator of BRCA1 and is critical for the efficient repair of DNA DSBs through HR. These findings will provide invaluable insight into how to exploit the interplay between SIRT2 and BRCA1 as a novel therapeutic approach for the prevention and treatment of cancer. Citation Format: Elizabeth Minten, Hui Zhang, Chunyang Li, PamelaSara Head, David S. Yu. The role of SIRT2 in BRCA1 regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1751.