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

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  • Yihan Peng

    (Beijing Institute of Lifeomics
    Renmin Hospital of Wuhan University
    The George Washington University School of Medicine and Health Science
    George Washington University School of Medicine and Health Sciences)

  • Qingchao Liao

    (Beijing Institute of Lifeomics
    Tianjin University of Science and Technology)

  • Wei Tan

    (The George Washington University School of Medicine and Health Science
    George Washington University School of Medicine and Health Sciences)

  • Changmin Peng

    (Renmin Hospital of Wuhan University
    The George Washington University School of Medicine and Health Science
    George Washington University School of Medicine and Health Sciences)

  • Zhaohua Hu

    (Beijing Institute of Lifeomics)

  • Yali Chen

    (Beijing Institute of Lifeomics)

  • Zhuqing Li

    (The George Washington University School of Medicine and Health Science
    George Washington University School of Medicine and Health Sciences)

  • Jing Li

    (The George Washington University School of Medicine and Health Science
    George Washington University School of Medicine and Health Sciences)

  • Bei Zhen

    (Beijing Institute of Lifeomics)

  • Wenge Zhu

    (The George Washington University School of Medicine and Health Science
    George Washington University School of Medicine and Health Sciences)

  • 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
    Renmin Hospital of Wuhan University
    The George Washington University School of Medicine and Health Science
    George Washington University School of Medicine and Health Sciences)

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.

Suggested Citation

  • 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 , 2019. "The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09232-8
    DOI: 10.1038/s41467-019-09232-8
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    Cited by:

    1. Sebastien Martinez & Shifei Wu & Michael Geuenich & Ahmad Malik & Ramona Weber & Tristan Woo & Amy Zhang & Gun Ho Jang & Dzana Dervovic & Khalid N. Al-Zahrani & Ricky Tsai & Nassima Fodil & Philippe G, 2024. "In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Zhenlei Zhang & Yufan Wu & Jinrong Fu & Xiujie Yu & Yang Su & Shikai Jia & Huili Cheng & Yan Shen & Xianghui He & Kai Ren & Xiangqian Zheng & Haixia Guan & Feng Rao & Li Zhao, 2024. "Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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