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

Qian Zhu, Jinzhou Huang, Hongyang Huang, Huan Li, Peiqiang Yi, Jake A. Kloeber, Jian Yuan, Yuping Chen, Min Deng, Kuntian Luo, Ming Gao, Guijie Guo, Xinyi Tu, Ping Yin, Yong Zhang, Jun Su, Jiayi Chen () and Zhenkun Lou ()
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Qian Zhu: Shanghai Jiaotong University School of Medicine
Jinzhou Huang: Mayo Clinic
Hongyang Huang: The University of Hong Kong
Huan Li: Shanghai Jiaotong University School of Medicine
Peiqiang Yi: Shanghai Jiaotong University School of Medicine
Jake A. Kloeber: Mayo Clinic
Jian Yuan: Tongji University School of medicine
Yuping Chen: Tongji University School of medicine
Min Deng: Mayo Clinic
Kuntian Luo: Mayo Clinic
Ming Gao: Mayo Clinic
Guijie Guo: Mayo Clinic
Xinyi Tu: Mayo Clinic
Ping Yin: Mayo Clinic
Yong Zhang: Mayo Clinic
Jun Su: Shanghai Jiaotong University School of Medicine
Jiayi Chen: Shanghai Jiaotong University School of Medicine
Zhenkun Lou: Mayo Clinic

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27048-3

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