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Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance
In response to DNA double-strand breaks (DSBs), repair proteins are recruited to the damaged sites. Ubiquitin signaling plays a critical role in coordinating protein recruitment during the DNA damage response. Here, we find that the microRNA biogenesis factor DGCR8 promotes tumor resistance to X-ray...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242032/ https://www.ncbi.nlm.nih.gov/pubmed/34188037 http://dx.doi.org/10.1038/s41467-021-24298-z |
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author | Hang, Qinglei Zeng, Liyong Wang, Li Nie, Litong Yao, Fan Teng, Hongqi Deng, Yalan Yap, Shannon Sun, Yutong Frank, Steven J. Chen, Junjie Ma, Li |
author_facet | Hang, Qinglei Zeng, Liyong Wang, Li Nie, Litong Yao, Fan Teng, Hongqi Deng, Yalan Yap, Shannon Sun, Yutong Frank, Steven J. Chen, Junjie Ma, Li |
author_sort | Hang, Qinglei |
collection | PubMed |
description | In response to DNA double-strand breaks (DSBs), repair proteins are recruited to the damaged sites. Ubiquitin signaling plays a critical role in coordinating protein recruitment during the DNA damage response. Here, we find that the microRNA biogenesis factor DGCR8 promotes tumor resistance to X-ray radiation independently of its Drosha-binding ability. Upon radiation, the kinase ATM and the deubiquitinase USP51 mediate the activation and stabilization of DGCR8 through phosphorylation and deubiquitination. Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8’s binding partner RNF168 to MDC1 and RNF8 at DSBs. This, in turn, promotes ubiquitination of histone H2A, repair of DSBs, and radioresistance. Altogether, these findings reveal the non-canonical function of DGCR8 in DSB repair and suggest that radiation treatment may result in therapy-induced tumor radioresistance through ATM- and USP51-mediated activation and upregulation of DGCR8. |
format | Online Article Text |
id | pubmed-8242032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82420322021-07-20 Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance Hang, Qinglei Zeng, Liyong Wang, Li Nie, Litong Yao, Fan Teng, Hongqi Deng, Yalan Yap, Shannon Sun, Yutong Frank, Steven J. Chen, Junjie Ma, Li Nat Commun Article In response to DNA double-strand breaks (DSBs), repair proteins are recruited to the damaged sites. Ubiquitin signaling plays a critical role in coordinating protein recruitment during the DNA damage response. Here, we find that the microRNA biogenesis factor DGCR8 promotes tumor resistance to X-ray radiation independently of its Drosha-binding ability. Upon radiation, the kinase ATM and the deubiquitinase USP51 mediate the activation and stabilization of DGCR8 through phosphorylation and deubiquitination. Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8’s binding partner RNF168 to MDC1 and RNF8 at DSBs. This, in turn, promotes ubiquitination of histone H2A, repair of DSBs, and radioresistance. Altogether, these findings reveal the non-canonical function of DGCR8 in DSB repair and suggest that radiation treatment may result in therapy-induced tumor radioresistance through ATM- and USP51-mediated activation and upregulation of DGCR8. Nature Publishing Group UK 2021-06-29 /pmc/articles/PMC8242032/ /pubmed/34188037 http://dx.doi.org/10.1038/s41467-021-24298-z Text en © The Author(s) 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 Hang, Qinglei Zeng, Liyong Wang, Li Nie, Litong Yao, Fan Teng, Hongqi Deng, Yalan Yap, Shannon Sun, Yutong Frank, Steven J. Chen, Junjie Ma, Li Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance |
title | Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance |
title_full | Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance |
title_fullStr | Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance |
title_full_unstemmed | Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance |
title_short | Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance |
title_sort | non-canonical function of dgcr8 in dna double-strand break repair signaling and tumor radioresistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242032/ https://www.ncbi.nlm.nih.gov/pubmed/34188037 http://dx.doi.org/10.1038/s41467-021-24298-z |
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