Abstract ES12-1: BRCA2 and control of transcription: R-loop dynamics

Abstract

Abstract Pathogenic germline mutations affecting the breast cancer genes, BRCA1 and BRCA2, predispose to cancers of the breast, ovary, and other tissues with a high penetrance. Cancer pathogenesis in mutation carriers has been linked to genomic instability following inactivation of the essential cellular functions of the encoded BRCA1 and BRCA2 proteins in DNA repair and the restoration of stalled DNA replication (reviewed in Venkitaraman, Science 343, 1470-5 (2014)). Here, I will discuss emerging evidence that links previously unrecognized functions of the BRCA proteins to carcinogenesis, focusing on BRCA2. Increasing evidence indicates that heterozygosity for pathogenic BRCA2 mutations suffices for carcinogenesis in experimental models and in human mutation carriers (eg., Skoulidis et al., Cancer Cell 18, 499-509 (2010); Maxwell et al., Nature Commun 8, 319 (2017); Huang et al., Cell 173, 355-370 (2018)). Heterozygous mis-sense mutations in BRCA2 may act trans-dominantly to interfere with the nuclear transport of BRCA2/RAD51 complexes (Jeyasekharan et al., Nature Str Mol Biol 20, 1191-8 (2013)). We have reported recently a gene-environment interaction that may modify carcinogenesis in BRCA2 mutation carriers, wherein exposure to aldehydes, a pervasive class of endogenous and environmental toxins, selectively proteolyzes BRCA2, inducing haploinsufficiency for DNA repair and replication fork stability in cells bearing heterozygous truncating BRCA2 mutations (Tan et al., Cell 169, 1105-18 (2017)). BRCA2-deficient cells accumulate unscheduled RNA-DNA hybrids (R-loops) and genomic damage through an unexpected role of BRCA2 in promoting the switch from promoter-proximal pausing to transcription elongation by RNA polymerase II (Shivji et al., Cell Rep 22, 1031-1039 (2018)). These emerging functions have implications for the pathogenesis and therapy of cancers arising in patients who carry BRCA2 mutations. Citation Format: Venkitaraman A. BRCA2 and control of transcription: R-loop dynamics [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 ES12-1.