The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors

Yihan Peng, Qingchao Liao, Wei Tan, Changmin Peng, Zhaohua Hu, Yali Chen, Zhuqing Li, Jing Li, Bei Zhen, Wenge Zhu, Xiangpan Li, Yi Yao, Qibin Song, Chengsheng Liu, Xiangdong Qi (), Fuchu He () and Huadong Pei ()
Additional contact information
Yihan Peng: Beijing Institute of Lifeomics
Qingchao Liao: Beijing Institute of Lifeomics
Wei Tan: The George Washington University School of Medicine and Health Science
Changmin Peng: Renmin Hospital of Wuhan University
Zhaohua Hu: Beijing Institute of Lifeomics
Yali Chen: Beijing Institute of Lifeomics
Zhuqing Li: The George Washington University School of Medicine and Health Science
Jing Li: The George Washington University School of Medicine and Health Science
Bei Zhen: Beijing Institute of Lifeomics
Wenge Zhu: The George Washington University School of Medicine and Health Science
Xiangpan Li: Renmin Hospital of Wuhan University
Yi Yao: Renmin Hospital of Wuhan University
Qibin Song: Renmin Hospital of Wuhan University
Chengsheng Liu: Aesthetic Surgery, Jingmei Cosmetic Surgery Clinic
Xiangdong Qi: General Hospital of Southern Theater Command
Fuchu He: Beijing Institute of Lifeomics
Huadong Pei: Beijing Institute of Lifeomics

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Poly-(ADP-ribose) polymerase inhibitors (PARPi) selectively kill breast and ovarian cancers with defects in homologous recombination (HR) caused by BRCA1/2 mutations. There is also clinical evidence for the utility of PARPi in breast and ovarian cancers without BRCA mutations, but the underlying mechanism is not clear. Here, we report that the deubiquitylating enzyme USP15 affects cancer cell response to PARPi by regulating HR. Mechanistically, USP15 is recruited to DNA double-strand breaks (DSBs) by MDC1, which requires the FHA domain of MDC1 and phosphorylated Ser678 of USP15. Subsequently, USP15 deubiquitinates BARD1 BRCT domain, and promotes BARD1-HP1γ interaction, resulting in BRCA1/BARD1 retention at DSBs. USP15 knockout mice exhibit genomic instability in vivo. Furthermore, cancer-associated USP15 mutations, with decreased USP15-BARD1 interaction, increases PARP inhibitor sensitivity in cancer cells. Thus, our results identify a novel regulator of HR, which is a potential biomarker for therapeutic treatment using PARP inhibitors in cancers.

Date: 2019
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DOI: 10.1038/s41467-019-09232-8

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