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

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, Bohan Ma, Yizeng Fan, Yang Gao, Haojie Huang () and Lei Li ()
Additional contact information
Jian Ma: The First Affiliated Hospital of Xi’an Jiaotong University
Yingke Zhou: Mayo Clinic College of Medicine and Science
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
Lei Li: The First Affiliated Hospital of Xi’an Jiaotong University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37499-5

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