PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation

Poly(ADP)-ribosylation (PARylation) regulates chromatin structure and recruits DNA repair proteins. Using single-molecule fluorescence microscopy to track topoisomerase I (TOP1) in live cells, we found that sustained PARylation blocked the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) in a simil...

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Autores principales: Sun, Yilun, Chen, Jiji, Huang, Shar-yin N., Su, Yijun P., Wang, Wenjie, Agama, Keli, Saha, Sourav, Jenkins, Lisa M., Pascal, John M., Pommier, Yves
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373905/
https://www.ncbi.nlm.nih.gov/pubmed/34408146
http://dx.doi.org/10.1038/s41467-021-25252-9
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author Sun, Yilun
Chen, Jiji
Huang, Shar-yin N.
Su, Yijun P.
Wang, Wenjie
Agama, Keli
Saha, Sourav
Jenkins, Lisa M.
Pascal, John M.
Pommier, Yves
author_facet Sun, Yilun
Chen, Jiji
Huang, Shar-yin N.
Su, Yijun P.
Wang, Wenjie
Agama, Keli
Saha, Sourav
Jenkins, Lisa M.
Pascal, John M.
Pommier, Yves
author_sort Sun, Yilun
collection PubMed
description Poly(ADP)-ribosylation (PARylation) regulates chromatin structure and recruits DNA repair proteins. Using single-molecule fluorescence microscopy to track topoisomerase I (TOP1) in live cells, we found that sustained PARylation blocked the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) in a similar fashion as inhibition of the ubiquitin-proteasome system (UPS). PARylation of TOP1-DPC was readily revealed by inhibiting poly(ADP-ribose) glycohydrolase (PARG), indicating the otherwise transient and reversible PARylation of the DPCs. As the UPS is a key repair mechanism for TOP1-DPCs, we investigated the impact of TOP1-DPC PARylation on the proteasome and found that the proteasome is unable to associate with and digest PARylated TOP1-DPCs. In addition, PARylation recruits the deubiquitylating enzyme USP7 to reverse the ubiquitylation of PARylated TOP1-DPCs. Our work identifies PARG as repair factor for TOP1-DPCs by enabling the proteasomal digestion of TOP1-DPCs. It also suggests the potential regulatory role of PARylation for the repair of a broad range of DPCs.
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spelling pubmed-83739052021-09-02 PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation Sun, Yilun Chen, Jiji Huang, Shar-yin N. Su, Yijun P. Wang, Wenjie Agama, Keli Saha, Sourav Jenkins, Lisa M. Pascal, John M. Pommier, Yves Nat Commun Article Poly(ADP)-ribosylation (PARylation) regulates chromatin structure and recruits DNA repair proteins. Using single-molecule fluorescence microscopy to track topoisomerase I (TOP1) in live cells, we found that sustained PARylation blocked the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) in a similar fashion as inhibition of the ubiquitin-proteasome system (UPS). PARylation of TOP1-DPC was readily revealed by inhibiting poly(ADP-ribose) glycohydrolase (PARG), indicating the otherwise transient and reversible PARylation of the DPCs. As the UPS is a key repair mechanism for TOP1-DPCs, we investigated the impact of TOP1-DPC PARylation on the proteasome and found that the proteasome is unable to associate with and digest PARylated TOP1-DPCs. In addition, PARylation recruits the deubiquitylating enzyme USP7 to reverse the ubiquitylation of PARylated TOP1-DPCs. Our work identifies PARG as repair factor for TOP1-DPCs by enabling the proteasomal digestion of TOP1-DPCs. It also suggests the potential regulatory role of PARylation for the repair of a broad range of DPCs. Nature Publishing Group UK 2021-08-18 /pmc/articles/PMC8373905/ /pubmed/34408146 http://dx.doi.org/10.1038/s41467-021-25252-9 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sun, Yilun
Chen, Jiji
Huang, Shar-yin N.
Su, Yijun P.
Wang, Wenjie
Agama, Keli
Saha, Sourav
Jenkins, Lisa M.
Pascal, John M.
Pommier, Yves
PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation
title PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation
title_full PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation
title_fullStr PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation
title_full_unstemmed PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation
title_short PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation
title_sort parylation prevents the proteasomal degradation of topoisomerase i dna-protein crosslinks and induces their deubiquitylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373905/
https://www.ncbi.nlm.nih.gov/pubmed/34408146
http://dx.doi.org/10.1038/s41467-021-25252-9
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