DePARylation is critical for S phase progression and cell survival

Litong Nie, Chao Wang, Min Huang, Xiaoguang Liu, Xu Feng, Mengfan Tang, Siting Li, Qinglei Hang, Hongqi Teng, Xi Shen, Li Ma, Boyi Gan, Junjie Chen

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S-phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.

Original languageEnglish (US)
JournaleLife
Volume12
DOIs
StatePublished - Apr 5 2024

Keywords

  • PARG
  • PARG inhibitor
  • PARP1
  • PARylation
  • biochemistry
  • cancer biology
  • chemical biology
  • nad
  • parg
  • parg inhibitor
  • parp inhibitor
  • parylation
  • ribosylation

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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