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DePARylation is critical for S phase progression and cell survival
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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418084/ https://www.ncbi.nlm.nih.gov/pubmed/37577639 http://dx.doi.org/10.1101/2023.07.31.551317 |
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author | Nie, Litong Wang, Chao Huang, Min Liu, Xiaoguang Feng, Xu Tang, Mengfan Li, Siting Hang, Qinglei Teng, Hongqi Shen, Xi Ma, Li Gan, Boyi Chen, Junjie |
author_facet | Nie, Litong Wang, Chao Huang, Min Liu, Xiaoguang Feng, Xu Tang, Mengfan Li, Siting Hang, Qinglei Teng, Hongqi Shen, Xi Ma, Li Gan, Boyi Chen, Junjie |
author_sort | Nie, Litong |
collection | PubMed |
description | 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. SIGNIFICANCE STATEMENT: Poly(ADP-ribosyl)ation is a reversible post-translational modification. Although PARG may have a protective effect against excessive PARP1 engagement, detailed knowledge of PARG’s mechanism of action remains elusive. Here, we showed that PARG participates in DNA replication, especially in Okazaki fragment maturation. Moreover, PARG level is critically important for cellular sensitivity to PARG inhibition, which is a valuable biomarker for PARGi-based therapy. |
format | Online Article Text |
id | pubmed-10418084 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-104180842023-08-12 DePARylation is critical for S phase progression and cell survival Nie, Litong Wang, Chao Huang, Min Liu, Xiaoguang Feng, Xu Tang, Mengfan Li, Siting Hang, Qinglei Teng, Hongqi Shen, Xi Ma, Li Gan, Boyi Chen, Junjie bioRxiv Article 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. SIGNIFICANCE STATEMENT: Poly(ADP-ribosyl)ation is a reversible post-translational modification. Although PARG may have a protective effect against excessive PARP1 engagement, detailed knowledge of PARG’s mechanism of action remains elusive. Here, we showed that PARG participates in DNA replication, especially in Okazaki fragment maturation. Moreover, PARG level is critically important for cellular sensitivity to PARG inhibition, which is a valuable biomarker for PARGi-based therapy. Cold Spring Harbor Laboratory 2023-10-06 /pmc/articles/PMC10418084/ /pubmed/37577639 http://dx.doi.org/10.1101/2023.07.31.551317 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Nie, Litong Wang, Chao Huang, Min Liu, Xiaoguang Feng, Xu Tang, Mengfan Li, Siting Hang, Qinglei Teng, Hongqi Shen, Xi Ma, Li Gan, Boyi Chen, Junjie DePARylation is critical for S phase progression and cell survival |
title | DePARylation is critical for S phase progression and cell survival |
title_full | DePARylation is critical for S phase progression and cell survival |
title_fullStr | DePARylation is critical for S phase progression and cell survival |
title_full_unstemmed | DePARylation is critical for S phase progression and cell survival |
title_short | DePARylation is critical for S phase progression and cell survival |
title_sort | deparylation is critical for s phase progression and cell survival |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418084/ https://www.ncbi.nlm.nih.gov/pubmed/37577639 http://dx.doi.org/10.1101/2023.07.31.551317 |
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