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USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma
Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC), and approximately 20% of patients experience treatment failure due to tumour radioresistance. However, the exact regulatory mechanism remains poorly understood. Here, we show that the deubiquitinase USP44 is hype...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789930/ https://www.ncbi.nlm.nih.gov/pubmed/35079021 http://dx.doi.org/10.1038/s41467-022-28158-2 |
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author | Chen, Yang Zhao, Yin Yang, Xiaojing Ren, Xianyue Huang, Shengyan Gong, Sha Tan, Xirong Li, Junyan He, Shiwei Li, Yingqin Hong, Xiaohong Li, Qian Ding, Cong Fang, Xueliang Ma, Jun Liu, Na |
author_facet | Chen, Yang Zhao, Yin Yang, Xiaojing Ren, Xianyue Huang, Shengyan Gong, Sha Tan, Xirong Li, Junyan He, Shiwei Li, Yingqin Hong, Xiaohong Li, Qian Ding, Cong Fang, Xueliang Ma, Jun Liu, Na |
author_sort | Chen, Yang |
collection | PubMed |
description | Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC), and approximately 20% of patients experience treatment failure due to tumour radioresistance. However, the exact regulatory mechanism remains poorly understood. Here, we show that the deubiquitinase USP44 is hypermethylated in NPC, which results in its downregulation. USP44 enhances the sensitivity of NPC cells to radiotherapy in vitro and in vivo. USP44 recruits and stabilizes the E3 ubiquitin ligase TRIM25 by removing its K48-linked polyubiquitin chains at Lys439, which further facilitates the degradation of Ku80 and inhibits its recruitment to DNA double-strand breaks (DSBs), thus enhancing DNA damage and inhibiting DNA repair via non-homologous end joining (NHEJ). Knockout of TRIM25 reverses the radiotherapy sensitization effect of USP44. Clinically, low expression of USP44 indicates a poor prognosis and facilitates tumour relapse in NPC patients. This study suggests the USP44-TRIM25-Ku80 axis provides potential therapeutic targets for NPC patients. |
format | Online Article Text |
id | pubmed-8789930 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87899302022-02-07 USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma Chen, Yang Zhao, Yin Yang, Xiaojing Ren, Xianyue Huang, Shengyan Gong, Sha Tan, Xirong Li, Junyan He, Shiwei Li, Yingqin Hong, Xiaohong Li, Qian Ding, Cong Fang, Xueliang Ma, Jun Liu, Na Nat Commun Article Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC), and approximately 20% of patients experience treatment failure due to tumour radioresistance. However, the exact regulatory mechanism remains poorly understood. Here, we show that the deubiquitinase USP44 is hypermethylated in NPC, which results in its downregulation. USP44 enhances the sensitivity of NPC cells to radiotherapy in vitro and in vivo. USP44 recruits and stabilizes the E3 ubiquitin ligase TRIM25 by removing its K48-linked polyubiquitin chains at Lys439, which further facilitates the degradation of Ku80 and inhibits its recruitment to DNA double-strand breaks (DSBs), thus enhancing DNA damage and inhibiting DNA repair via non-homologous end joining (NHEJ). Knockout of TRIM25 reverses the radiotherapy sensitization effect of USP44. Clinically, low expression of USP44 indicates a poor prognosis and facilitates tumour relapse in NPC patients. This study suggests the USP44-TRIM25-Ku80 axis provides potential therapeutic targets for NPC patients. Nature Publishing Group UK 2022-01-25 /pmc/articles/PMC8789930/ /pubmed/35079021 http://dx.doi.org/10.1038/s41467-022-28158-2 Text en © The Author(s) 2022 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 Chen, Yang Zhao, Yin Yang, Xiaojing Ren, Xianyue Huang, Shengyan Gong, Sha Tan, Xirong Li, Junyan He, Shiwei Li, Yingqin Hong, Xiaohong Li, Qian Ding, Cong Fang, Xueliang Ma, Jun Liu, Na USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma |
title | USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma |
title_full | USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma |
title_fullStr | USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma |
title_full_unstemmed | USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma |
title_short | USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma |
title_sort | usp44 regulates irradiation-induced dna double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789930/ https://www.ncbi.nlm.nih.gov/pubmed/35079021 http://dx.doi.org/10.1038/s41467-022-28158-2 |
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