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The deubiquitinase OTUD5 regulates Ku80 stability and non-homologous end joining

  • Fangzhou Li
  • Qianqian Sun
  • Kun Liu
  • Haichao Han
  • Ning Lin
  • Zhongyi Cheng
  • Yueming Cai
  • Feng Tian
  • Zebin Mao
  • Tanjun Tong
  • Wenhui ZhaoEmail author
Original Article
  • 150 Downloads

Abstract

The ability of cells to repair DNA double-strand breaks (DSBs) is important for maintaining genome stability and eliminating oncogenic DNA lesions. Two distinct and complementary pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), are employed by mammalian cells to repair DNA DSBs. Each pathway is tightly controlled in response to increased DSBs. The Ku heterodimer has been shown to play a regulatory role in NHEJ repair. Ku80 ubiquitination contributes to the selection of a DSB repair pathway by causing the removal of Ku heterodimers from DSB sites. However, whether Ku80 deubiquitination also plays a role in regulating DSB repair is unknown. To address this question, we performed a comprehensive study of the deubiquitinase specific for Ku80, and our study showed that the deubiquitinase OTUD5 serves as an important regulator of NHEJ repair by increasing the stability of Ku80. Further studies revealed that OTUD5 depletion impaired NHEJ repair, and hence reduced overall DSB repair. Furthermore, OTUD5-depleted cells displayed excess end resection; as a result, HR repair was facilitated by OTUD5 depletion during the S/G2 phase. In summary, our study demonstrates that OTUD5 is a specific deubiquitinase for Ku80 and establishes OTUD5 as an important and positive regulator of NHEJ repair.

Keywords

XRCC5 DUBA DNA lesion Deubiquitinases library DNA damage response 

Notes

Acknowledgements

We are grateful to Dr. Jiadong Wang for his suggestion and help. We thank Qihua He for her suggestion and help, and Center of Medical and Health Analysis, Peking University, for confocal microscopy. We appreciate the ALENABIO (Xi’an, China) Company (http://www.alenabio.com) for the pathological micro-tissues (Cat. No. BC03119a). We deeply appreciate help from Ning Kon for editing our manuscript.

Author contributions

FL and WZ, conceived and designed the study that led to the submission, acquired data, and interpreted the results; FL performed the experiment; QS, KL, HH, QH, ZC, YM, and FT participated in the revision of the manuscript; ZM and TT approved the final version; and WZ was the corresponding author. The authors declare that they have no conflicts of interest associated with the contents of this article.

Funding

Wenhui Zhao was supported by the National Natural Science Foundation of China (Grant No. 85141044).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Availability of data and material

All of the data and material in this paper are available upon request.

Supplementary material

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Fangzhou Li
    • 1
  • Qianqian Sun
    • 1
  • Kun Liu
    • 1
  • Haichao Han
    • 1
  • Ning Lin
    • 1
  • Zhongyi Cheng
    • 3
  • Yueming Cai
    • 4
  • Feng Tian
    • 2
  • Zebin Mao
    • 1
  • Tanjun Tong
    • 1
  • Wenhui Zhao
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular Biology, Peking University Health Science CenterBeijing Key Laboratory of Protein Posttranslational Modifications and Cell FunctionBeijingChina
  2. 2.Department of Laboratory Animal SciencePeking University Health Science CenterBeijingChina
  3. 3.Jingjie PTM BioLab, Co. Ltd, Hangzhou Economic and Technological Development AreaHangzhouChina
  4. 4.Rheumatic Immunology DepartmentPeking University Shenzhen HospitalShenzhenChina

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