Abstract 2759: USP21 stabilizes the BRCA2/Rad51 complex to ensure cancer genome maintenance

Abstract

Abstract Cancer is a disease of defective genome maintenance. Paradoxically, however, tumor growth relies on efficient DNA repair to mitigate the detrimental impact of replication-associated DNA double-strand breaks (DSBs). Deleterious mutations in BRCA2, a tumor suppressor that promotes homologous recombination (HR), consequently result in increased susceptibility to genotoxic stress in rapidly dividing tumor cells. While these findings underscore the importance of tightly controlled BRCA2 function for tumor growth, little is known about the factors that regulate this process. Here, we establish the ubiquitin-specific protease USP21 as a positive regulator of BRCA2 stability. USP21 interacts with, deubiquitinates and stabilizes the BRCA2/Rad51 complex and promotes efficient Rad51 loading to DSBs. As a result, depletion of USP21 decreases HR efficiency, causes an increase in DNA damage load and impairs tumor cell survival. Importantly, BRCA2 overexpression partially restores the USP21-associated HR defect. Moreover, we show that USP21 is overexpressed in hepatocellular carcinoma (HCC), where it promotes BRCA2 stability and inversely correlates with patient survival. These findings demonstrate a novel deubiquitination mechanism to control BRCA2 levels and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors. Citation Format: Jinping Liu, Alex J. Kruswick, Hien Dang, Andy D. Tran, Xin W. Wang, Philipp Philipp. USP21 stabilizes the BRCA2/Rad51 complex to ensure cancer genome maintenance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2759.