Abstract 3013: RNF126 promotes homologous recombination via regulating E2F1-mediated BRCA1 expression

Abstract Abstract: Homologous recombination (HR)-mediated DNA double-strand break repair is important for cell proliferation, cancer prevention and cancer therapy resistance. HR protein BRCA1 is one of the most important breast/ovarian cancer suppressor genes. Lower expression of BRCA1 has been frequently observed in a broad spectrum of human cancers, particularly sporadic breast/ovarian cancers. However, the mechanisms governing BRCA1 expression is elusive. RNF126 is an E3 ubiquitin ligase and is mapped to chromosome 19 p13.3 which is a commonly deleted region in ovarian cancers. In addition, high-resolution 19p13.2-13.3 allelotyping of breast carcinomas demonstrates frequent loss of heterozygosity. The Cancer Genome Atlas (TCGA) data suggested that RNF126 depletion present in a broad spectrum of human tumors, particularly ovarian cancers. Although a recent study suggested that RNF126 promote cell growth, the function of RNF126 remains largely unknown. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 10 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Last, RNF126 depletion leads to the increased sensitivity to ionizing radiation (IR) and poly (ADP-ribose) polymerase (PARP) inhibitor. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through the positive regulation on BRCA1 expression by binding to E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for the cancer treatment. Key words: Homologous recombination, RNF126, E2F1, BRCA1 Citation Format: Ying Wang, Ou Deng, Zhihui Feng, Zhanwen Du, Xiahui Xiong, Ceshi Chen, Zhefu Ma, Junran Zhang. RNF126 promotes homologous recombination via regulating E2F1-mediated BRCA1 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3013. doi:10.1158/1538-7445.AM2015-3013