Abstract 6216: Pre-ribosomal RNA mediates HR repair via the BRCA1/BARD1 complex

Abstract

Abstract The BRCA1/BARD1 complex plays a key role in DNA double-stand break (DSB) repair in both somatic cells and germ cells. However, the underlying molecular mechanism by which this complex mediates DSB repair remains elusive. Here, we show that the recruitment of the BRCA1/BARD1 complex to the unsynapsed axis of the XY body in male germ cells is mediated by pre-rRNA. Similarly, the BRCA1/BARD1 complex associates with pre-rRNA in somatic cells, which targets the BRCA1/BARD1 complex to DSBs. The interactions between the BRCT domains of the BRCA1/BARD1 complex and pre-rRNA induces liquid-liquid phase separations, which may be the molecular basis of DSB-induced nuclear foci formation of the BRCA1/BARD1 complex. Pre-rRNA also mediates BRCA1-dependent homologous recombination (HR). Cancer-associated mutations in the BRCT domains of BRCA1 and BARD1 abolish the interaction with pre-rRNA. We developed novel RNA pol I inhibitors to suppress pre-rRNA biogenesis, which not only abolished HR repair but also sensitized tumor cells to PARP inhibitor treatment. Collectively, this study reveals that pre-rRNA is a functional partner of the BRCA1/BARD1 complex in the DSB repair. It is also a potential therapeutic target for cancer therapy. Citation Format: Duo Wu, Huang Huang, Tenglong Chen, Xiaochen Gai, Song Liu, Hu He, Song Shi, Xiaochun Yu. Pre-ribosomal RNA mediates HR repair via the BRCA1/BARD1 complex. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6216.