RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination

Qian Zhu,Ming Gao,Min Deng,Peiqiang Yi,Jinzhou Huang,Ping Yin,Jiayi Chen,Xinyi Tu,Guijie Guo,Jian Yuan,Yong Zhang,Yuping Chen,Huan Li,Kuntian Luo,Jun Su,Zhenkun Lou,Jake A Kloeber,Hongyang Huang

doi:10.1038/s41467-021-27048-3

Abstract

BRCA1-BARD1 heterodimers act in multiple steps during homologous recombination (HR) to ensure the prompt repair of DNA double strand breaks. Dysfunction of the BRCA1 pathway enhances the therapeutic efficiency of poly-(ADP-ribose) polymerase inhibitors (PARPi) in cancers, but the molecular mechanisms underlying this sensitization to PARPi are not fully understood. Here, we show that cancer cell sensitivity to PARPi is promoted by the ring between ring fingers (RBR) protein RNF19A. We demonstrate that RNF19A suppresses HR by ubiquitinating BARD1, which leads to dissociation of BRCA1-BARD1 complex and exposure of a nuclear export sequence in BARD1 that is otherwise masked by BRCA1, resulting in the export of BARD1 to the cytoplasm. We provide evidence that high RNF19A expression in breast cancer compromises HR and increases sensitivity to PARPi. We propose that RNF19A modulates the cancer cell response to PARPi by negatively regulating the BRCA1-BARD1 complex and inhibiting HR-mediated DNA repair.

Highlights

BRCA1-BRCA1-associated RING domain-1 (BARD1) heterodimers act in multiple steps during homologous recombination (HR) to ensure the prompt repair of DNA double strand breaks
We found a potential role of RNF19A in the DNA damage response (DDR)
Because we observed that RNF19A regulates BARD1 ubiquitination and BRCA1/BARD1 retention at double-strand breaks (DSBs), we explored whether RNF19A would affect BRCA1/ BARD1 interaction

Summary

Introduction

BRCA1-BARD1 heterodimers act in multiple steps during homologous recombination (HR) to ensure the prompt repair of DNA double strand breaks. (BARD1) structurally links to BRCA1 through their conserved RING finger domains at the N-terminus, especially residues 1–109 of BRCA1 and residues 26–119 of BARD1, thereby carrying out various functions including DNA repair, substrate ubiquitination, and mRNA process regulation[7,8]. Both genes have been identified as tumor suppressors[9,10]. BARD1 contains a nuclear export sequence (NES) that is masked by BRCA1 binding[20] This has functional implications since BRCA1/BARD1 must localize to the nucleus to participate in HR and suppress tumorigenesis, whereas their dissociation may lead to nuclear export and dysfunctional HR repair[21].

Methods

Results

Conclusion