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USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response.

Yunhui Li1,2, Kuntian Luo1,2,3, Yujiao Yin1,2

  • 1Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.

Nature Communications
|June 2, 2017
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Summary
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USP13 deubiquitinates RAP80, promoting DNA repair and BRCA1 complex formation. This deubiquitinase regulates DNA damage response, impacting ovarian cancer cell sensitivity to chemotherapy.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • BRCA1 is crucial for genomic stability, regulating DNA repair and other cellular processes.
  • Receptor-associated protein 80 (RAP80) facilitates BRCA1 recruitment to DNA double-strand breaks (DSBs) for DNA damage response (DDR).
  • The precise regulation of the RAP80-BRCA1 complex remains incompletely understood.

Purpose of the Study:

  • To investigate the role of USP13 in regulating the RAP80-BRCA1 complex and DNA damage response.
  • To elucidate the mechanism by which USP13 influences DDR.
  • To determine the therapeutic implications of USP13 activity in ovarian cancer.

Main Methods:

  • Investigated USP13's interaction with RAP80 and its role in DDR.
  • Examined USP13 phosphorylation by ATM and its localization to DSBs.
  • Assessed the effect of USP13 depletion or overexpression on ovarian cancer cell sensitivity to DNA damaging agents and PARP inhibitors.

Main Results:

  • USP13, a deubiquitinase, targets RAP80 for deubiquitination, promoting RAP80-BRCA1 complex formation at DSBs.
  • ATM-mediated phosphorylation of USP13 enhances its recruitment to DSBs following DNA damage.
  • USP13 activity is essential for proper DDR, and its modulation affects ovarian cancer cell chemosensitivity.

Conclusions:

  • USP13 acts as a key regulator of DNA repair by controlling RAP80 deubiquitination and subsequent BRCA1 complex assembly.
  • A novel phosphorylation-deubiquitination signaling axis involving ATM, USP13, and RAP80 dynamically regulates DDR.
  • USP13 modulation offers a potential therapeutic strategy for ovarian cancer, influencing response to chemotherapy and PARP inhibitors.