ADP-ribosylhydrolases: from DNA damage repair to COVID-19

ADP-核糖基水解酶:从DNA损伤修复到2019新型冠状病毒肺炎

Abstract

Adenosine diphosphate (ADP)-ribosylation is a unique post-translational modification that regulates many biological processes, such as DNA damage repair. During DNA repair, ADP-ribosylation needs to be reversed by ADP-ribosylhydrolases. A group of ADP-ribosylhydrolases have a catalytic domain, namely the macrodomain, which is conserved in evolution from prokaryotes to humans. Not all macrodomains remove ADP-ribosylation. One set of macrodomains loses enzymatic activity and only binds to ADP-ribose (ADPR). Here, we summarize the biological functions of these macrodomains in DNA damage repair and compare the structure of enzymatically active and inactive macrodomains. Moreover, small molecular inhibitors have been developed that target macrodomains to suppress DNA damage repair and tumor growth. Macrodomain proteins are also expressed in pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, these domains may not be directly involved in DNA damage repair in the hosts or pathogens. Instead, they play key roles in pathogen replication. Thus, by targeting macrodomains it may be possible to treat pathogen-induced diseases, such as coronavirus disease 2019 (COVID-19).

概要

ADP-核糖基化是一种独特的翻译后修饰,调控众多生物反应进程,亦在DNA损伤修复中发挥重要功能。在DNA修复的过程中,ADP-核糖基化修饰能够被可逆去除。已有研究 表明,一组含有Macro结构域的ADP-核糖基水解酶能够去除ADP-核糖基化修饰。本文将总结含有Macro结构域的ADP-核糖基水解酶的催化反应机制以及它们在DNA损伤修复中 的功能。此外,本文将比较具有催化活性和无催化活性的Macro结构域的结构差异。Macro结构域在进化过程中高度保守,在多种病毒中均发现Macro结构域的存在,例如,严重急 性呼吸综合症冠状病毒2(SARS-CoV-2)。病毒Macro结构域蛋白具有共同的结构特征,在病毒复制过程中发挥重要作用,靶向病毒Macro结构域的药物设计有可能用于治疗病毒感 染引发的疾病,例如,2019新型冠状病毒肺炎(COVID-19)。

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Acknowledgments

The research was supported by the National Natural Science Foundation of China (No. 81874160), the Foundation of Hebei Educational Committee (No. ZD2020183), the Ministry of Education Chunhui Project, the Hebei Province Foundation for Returned Overseas Chinese Scholars (No. C20200303), and the research funds from Westlake University, Hangzhou, China.

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Lily YU wrote the manuscript and summarized the relevant literature. Xiuhua LIU and Xiaochun YU provided the theme and design, and edited the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Xiuhua Liu or Xiaochun Yu.

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Lily YU, Xiuhua LIU, and Xiaochun YU declare that they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Yu, L., Liu, X. & Yu, X. ADP-ribosylhydrolases: from DNA damage repair to COVID-19. J. Zhejiang Univ. Sci. B 22, 21–30 (2021). https://doi.org/10.1631/jzus.B2000319

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Key words

  • DNA damage repair
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • Adenosine diphosphate (ADP)-ribosylation
  • Macrodomain
  • ADP-ribosylhydrolase
  • deADP-ribosylation

关键词

  • DNA损伤修复
  • ADP-核糖基化
  • 去ADP-核糖基化
  • Macro结构域
  • ADP-核糖基水解酶
  • 严重急性呼吸综合症冠状病毒2(SARS-CoV-2)