A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability

RPA is a master regulator of DNA metabolism and RPA availability acts as a rate-limiting factor. While numerous studies focused on the post-translational regulations of RPA for its functions, little is known regarding how RPA availability is controlled. Here we identify a novel lncRNA Discn as the g...

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Autores principales: Wang, Lin, Li, Jingzheng, Zhou, Hu, Zhang, Weidao, Gao, Jing, Zheng, Ping
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/PMC8458541/
https://www.ncbi.nlm.nih.gov/pubmed/34552092
http://dx.doi.org/10.1038/s41467-021-25827-6
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author Wang, Lin
Li, Jingzheng
Zhou, Hu
Zhang, Weidao
Gao, Jing
Zheng, Ping
author_facet Wang, Lin
Li, Jingzheng
Zhou, Hu
Zhang, Weidao
Gao, Jing
Zheng, Ping
author_sort Wang, Lin
collection PubMed
description RPA is a master regulator of DNA metabolism and RPA availability acts as a rate-limiting factor. While numerous studies focused on the post-translational regulations of RPA for its functions, little is known regarding how RPA availability is controlled. Here we identify a novel lncRNA Discn as the guardian of RPA availability in stem cells. Discn is induced upon genotoxic stress and binds to neucleolin (NCL) in the nucleolus. This prevents NCL from translocation into nucleoplasm and avoids undesirable NCL-mediated RPA sequestration. Thus, Discn-NCL-RPA pathway preserves a sufficient RPA pool for DNA replication stress response and repair. Discn loss causes massive genome instability in mouse embryonic stem cells and neural stem/progenigor cells. Mice depleted of Discn display newborn death and brain dysfunctions due to DNA damage accumulation and associated inflammatory reactions. Our findings uncover a key regulator of DNA metabolism and provide new clue to understand the chemoresistance in cancer treatment.
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spelling pubmed-84585412021-10-07 A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability Wang, Lin Li, Jingzheng Zhou, Hu Zhang, Weidao Gao, Jing Zheng, Ping Nat Commun Article RPA is a master regulator of DNA metabolism and RPA availability acts as a rate-limiting factor. While numerous studies focused on the post-translational regulations of RPA for its functions, little is known regarding how RPA availability is controlled. Here we identify a novel lncRNA Discn as the guardian of RPA availability in stem cells. Discn is induced upon genotoxic stress and binds to neucleolin (NCL) in the nucleolus. This prevents NCL from translocation into nucleoplasm and avoids undesirable NCL-mediated RPA sequestration. Thus, Discn-NCL-RPA pathway preserves a sufficient RPA pool for DNA replication stress response and repair. Discn loss causes massive genome instability in mouse embryonic stem cells and neural stem/progenigor cells. Mice depleted of Discn display newborn death and brain dysfunctions due to DNA damage accumulation and associated inflammatory reactions. Our findings uncover a key regulator of DNA metabolism and provide new clue to understand the chemoresistance in cancer treatment. Nature Publishing Group UK 2021-09-22 /pmc/articles/PMC8458541/ /pubmed/34552092 http://dx.doi.org/10.1038/s41467-021-25827-6 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
Wang, Lin
Li, Jingzheng
Zhou, Hu
Zhang, Weidao
Gao, Jing
Zheng, Ping
A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability
title A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability
title_full A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability
title_fullStr A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability
title_full_unstemmed A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability
title_short A novel lncRNA Discn fine-tunes replication protein A (RPA) availability to promote genomic stability
title_sort novel lncrna discn fine-tunes replication protein a (rpa) availability to promote genomic stability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458541/
https://www.ncbi.nlm.nih.gov/pubmed/34552092
http://dx.doi.org/10.1038/s41467-021-25827-6
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