Abstract P1-06-01: Regulation of BRCA1 by SIRT2

We are constantly exposed to a variety of both external and internal DNA damaging agents, such as UV light from the sun and reactive oxygen species created as by-products of aerobic respiration. As a result, our DNA accumulates thousands of instances of damage per cell per day. DNA damage response (DDR) pathways, which include DNA repair and cell-cycle checkpoints, are responsible for the repair of DNA damage and are critical for protecting against mutagenesis and maintaining genome integrity. DNA double-stranded breaks (DSBs) are the most deleterious type of DNA damage and are repaired by one of two pathways: Non-homologous end-joining (NHEJ), an error-prone mechanism of repair active throughout the entire cell cycle, or homologous recombination (HR), considered to be an 9error-free9 method for DSB repair that occurs in the S and G2 phases of the cell cycle. Deficiencies in NHEJ or HR can result in genomic instability via genomic incorporation of chromosomal aberrations, which can ultimately lead to an increased risk of cancer. However, in many cases, the mechanisms by which defects in these pathways lead to an increased risk of developing cancer is unknown, making preventative care and treatment of resulting cancers more difficult. Breast Cancer 1 (BRCA1), an established tumor suppressor, is a protein necessary for the proper repair of DNA DSBs through the HR pathway. Defects in BRCA1, whether genetically inherited or spontaneously developed, have been linked to different types of cancer in both men and women, including breast, ovarian, and pancreatic cancer. Yet, the regulation of BRCA1 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 SIRT2, a class III NAD+ dependent histone deacetylase and putative human tumor suppressor, plays a crucial role in the DDR and repair of DNA DSBs. We have shown that depletion of SIRT2 impairs HR and increases cell sensitivity to ionizing radiation in a deacetylase-dependent manner. A mass spectrometry analysis showed SIRT2 interacts with several proteins involved in DDR, including BRCA1. We validated the interaction between SIRT2 and BRCA1 and found SIRT2 deacetylates BRCA1 both in vitro and in cells. Depletion of SIRT2 and subsequent deacetylation of BRCA1 decreases BRCA1 protein levels in cells, impairing HR. Our results show SIRT2 is a novel regulator of BRCA1 and is critical for the repair of DNA DSBs through HR. These findings provide invaluable insights into how to exploit the interplay between SIRT2 and BRCA1 as a novel therapeutic approach for the prevention and treatment of cancer. Citation Format: Minten EV, Zhang H, Li C, Head PE, Yu DS. Regulation of BRCA1 by SIRT2 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-01.