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TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks
53BP1 promotes nonhomologous end joining (NHEJ) over homologous recombination (HR) repair by mediating inactivation of DNA end resection. Ubiquitination plays an important role in regulating dissociation of 53BP1 from DNA double-strand breaks (DSBs). However, how this process is regulated remains po...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066190/ https://www.ncbi.nlm.nih.gov/pubmed/37002234 http://dx.doi.org/10.1038/s41467-023-37499-5 |
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author | Ma, Jian Zhou, Yingke Pan, Penglin Yu, Haixin Wang, Zixi Li, Lei Lily Wang, Bing Yan, Yuqian Pan, Yunqian Ye, Qi Liu, Tianjie Feng, Xiaoyu Xu, Shan Wang, Ke Wang, Xinyang Jian, Yanlin Ma, Bohan Fan, Yizeng Gao, Yang Huang, Haojie Li, Lei |
author_facet | Ma, Jian Zhou, Yingke Pan, Penglin Yu, Haixin Wang, Zixi Li, Lei Lily Wang, Bing Yan, Yuqian Pan, Yunqian Ye, Qi Liu, Tianjie Feng, Xiaoyu Xu, Shan Wang, Ke Wang, Xinyang Jian, Yanlin Ma, Bohan Fan, Yizeng Gao, Yang Huang, Haojie Li, Lei |
author_sort | Ma, Jian |
collection | PubMed |
description | 53BP1 promotes nonhomologous end joining (NHEJ) over homologous recombination (HR) repair by mediating inactivation of DNA end resection. Ubiquitination plays an important role in regulating dissociation of 53BP1 from DNA double-strand breaks (DSBs). However, how this process is regulated remains poorly understood. Here, we demonstrate that TRABID deubiquitinase binds to 53BP1 at endogenous level and regulates 53BP1 retention at DSB sites. TRABID deubiquitinates K29-linked polyubiquitination of 53BP1 mediated by E3 ubiquitin ligase SPOP and prevents 53BP1 dissociation from DSBs, consequently inducing HR defects and chromosomal instability. Prostate cancer cells with TRABID overexpression exhibit a high sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Our work shows that TRABID facilitates NHEJ repair over HR during DNA repair by inducing prolonged 53BP1 retention at DSB sites, suggesting that TRABID overexpression may predict HR deficiency and the potential therapeutic use of PARP inhibitors in prostate cancer. |
format | Online Article Text |
id | pubmed-10066190 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100661902023-04-02 TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks Ma, Jian Zhou, Yingke Pan, Penglin Yu, Haixin Wang, Zixi Li, Lei Lily Wang, Bing Yan, Yuqian Pan, Yunqian Ye, Qi Liu, Tianjie Feng, Xiaoyu Xu, Shan Wang, Ke Wang, Xinyang Jian, Yanlin Ma, Bohan Fan, Yizeng Gao, Yang Huang, Haojie Li, Lei Nat Commun Article 53BP1 promotes nonhomologous end joining (NHEJ) over homologous recombination (HR) repair by mediating inactivation of DNA end resection. Ubiquitination plays an important role in regulating dissociation of 53BP1 from DNA double-strand breaks (DSBs). However, how this process is regulated remains poorly understood. Here, we demonstrate that TRABID deubiquitinase binds to 53BP1 at endogenous level and regulates 53BP1 retention at DSB sites. TRABID deubiquitinates K29-linked polyubiquitination of 53BP1 mediated by E3 ubiquitin ligase SPOP and prevents 53BP1 dissociation from DSBs, consequently inducing HR defects and chromosomal instability. Prostate cancer cells with TRABID overexpression exhibit a high sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Our work shows that TRABID facilitates NHEJ repair over HR during DNA repair by inducing prolonged 53BP1 retention at DSB sites, suggesting that TRABID overexpression may predict HR deficiency and the potential therapeutic use of PARP inhibitors in prostate cancer. Nature Publishing Group UK 2023-03-31 /pmc/articles/PMC10066190/ /pubmed/37002234 http://dx.doi.org/10.1038/s41467-023-37499-5 Text en © The Author(s) 2023 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 Ma, Jian Zhou, Yingke Pan, Penglin Yu, Haixin Wang, Zixi Li, Lei Lily Wang, Bing Yan, Yuqian Pan, Yunqian Ye, Qi Liu, Tianjie Feng, Xiaoyu Xu, Shan Wang, Ke Wang, Xinyang Jian, Yanlin Ma, Bohan Fan, Yizeng Gao, Yang Huang, Haojie Li, Lei TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks |
title | TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks |
title_full | TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks |
title_fullStr | TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks |
title_full_unstemmed | TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks |
title_short | TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks |
title_sort | trabid overexpression enables synthetic lethality to parp inhibitor via prolonging 53bp1 retention at double-strand breaks |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066190/ https://www.ncbi.nlm.nih.gov/pubmed/37002234 http://dx.doi.org/10.1038/s41467-023-37499-5 |
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