Abstract A38: A functional connection between the SWI/SNF-BAF ATPase BRG1 and the tumor suppressor BRCA1 in DNA damage response

Abstract

Abstract We and others have shown that the SWI/SNF (BAF) chromatin remodeling complex plays a role in the repair of UV-induced DNA damage. It was proposed that chromatin remodeling activities are utilized to increase the accessibility of NER machinery and checkpoint factors to the damaged DNA. It was demonstrated recently that BRCA1 contributes to UV damage response by promoting photoproduct excision, triggering post-UV checkpoint activation and post replicative repair. In this study, we show that BRCA1 rapidly binds to UV damage sites when cells are undergoing DNA synthesis. In contrast, two phosphorylated forms of BRCA1 do not accumulate at sites of UV damage. Depletion of BRG1, a core subunit of the human SWI/SNF-BAF complex, impairs the recruitment of BRCA1 to the damage sites and attenuates DNA damage induced BRCA1 phosphorylation. At UV lesions-stalled replication forks, BRG1 promotes RPA phosphorylation in response to UV irradiation, since UV-induced phosphorylation of chromatin bound RPA drops significantly when BRG1 is depleted in human cells. In addition, activation of ATR/ATM is attenuated when BRG1 is depleted. We propose that BRG1 functions upstream of BRCA1 and modulates its response to UV irradiation. Citation Format: Ling Zhang, Hua Chen, Feng Gong. A functional connection between the SWI/SNF-BAF ATPase BRG1 and the tumor suppressor BRCA1 in DNA damage response. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A38.