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TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks

Author

Listed:
  • Jian Ma

    (The First Affiliated Hospital of Xi’an Jiaotong University
    Mayo Clinic College of Medicine and Science)

  • Yingke Zhou

    (Mayo Clinic College of Medicine and Science
    Union Hospital, Tongji Medical College, Huazhong University of Science and Technology)

  • Penglin Pan

    (Union Hospital, Tongji Medical College, Huazhong University of Science and Technology)

  • Haixin Yu

    (Huazhong University of Science and Technology)

  • Zixi Wang

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Lei Lily Li

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Bing Wang

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Yuqian Yan

    (Mayo Clinic College of Medicine and Science)

  • Yunqian Pan

    (Mayo Clinic College of Medicine and Science)

  • Qi Ye

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Tianjie Liu

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Xiaoyu Feng

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Shan Xu

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Ke Wang

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Xinyang Wang

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Yanlin Jian

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Bohan Ma

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Yizeng Fan

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Yang Gao

    (The First Affiliated Hospital of Xi’an Jiaotong University)

  • Haojie Huang

    (Mayo Clinic College of Medicine and Science
    Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science
    Mayo Clinic College of Medicine and Science)

  • Lei Li

    (The First Affiliated Hospital of Xi’an Jiaotong University)

Abstract

53BP1 promotes nonhomologous end joining (NHEJ) over homologous recombination (HR) repair by mediating inactivation of DNA end resection. Ubiquitination plays an important role in regulating dissociation of 53BP1 from DNA double-strand breaks (DSBs). However, how this process is regulated remains poorly understood. Here, we demonstrate that TRABID deubiquitinase binds to 53BP1 at endogenous level and regulates 53BP1 retention at DSB sites. TRABID deubiquitinates K29-linked polyubiquitination of 53BP1 mediated by E3 ubiquitin ligase SPOP and prevents 53BP1 dissociation from DSBs, consequently inducing HR defects and chromosomal instability. Prostate cancer cells with TRABID overexpression exhibit a high sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Our work shows that TRABID facilitates NHEJ repair over HR during DNA repair by inducing prolonged 53BP1 retention at DSB sites, suggesting that TRABID overexpression may predict HR deficiency and the potential therapeutic use of PARP inhibitors in prostate cancer.

Suggested Citation

  • Jian Ma & Yingke Zhou & Penglin Pan & Haixin Yu & Zixi Wang & Lei Lily Li & Bing Wang & Yuqian Yan & Yunqian Pan & Qi Ye & Tianjie Liu & Xiaoyu Feng & Shan Xu & Ke Wang & Xinyang Wang & Yanlin Jian & , 2023. "TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37499-5
    DOI: 10.1038/s41467-023-37499-5
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    References listed on IDEAS

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