1. RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination
- Author
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Yong Zhang, Jiayi Chen, Qian Zhu, Min Deng, Peiqiang Yi, Hongyang Huang, Xinyi Tu, Jake A. Kloeber, Huan Li, Ming Gao, Guijie Guo, Yuping Chen, Jian Yuan, Jinzhou Huang, Zhenkun Lou, Kuntian Luo, Ping Yin, and Jun Su
- Subjects
Ubiquitylation ,endocrine system diseases ,Carcinogenesis ,DNA repair ,Ubiquitin-Protein Ligases ,Science ,General Physics and Astronomy ,Breast Neoplasms ,Poly(ADP-ribose) Polymerase Inhibitors ,Article ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,Breast cancer ,Ubiquitin ,BARD1 ,Humans ,Homologous recombination ,Nuclear export signal ,skin and connective tissue diseases ,Polymerase ,Multidisciplinary ,biology ,BRCA1 Protein ,Tumor Suppressor Proteins ,Ubiquitination ,General Chemistry ,Cell biology ,chemistry ,Cancer cell ,biology.protein ,Female ,Protein Multimerization ,RING Finger Domains ,DNA ,DNA Damage ,Protein Binding - 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., BRCA1 dysfunction sensitizes cancer cells to PARP inhibitors (PARPi) but the underlying mechanism is unclear. Here, the authors identify RNF19A as a determinant of PARPi sensitivity, showing that RNF19A ubiquitinates BARD1, negatively regulates the BRCA1-BARD1 complex, and inhibits homologous recombination.
- Published
- 2021