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lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence

Long noncoding RNAs (lncRNAs) undergo extensive alternative splicing, but little is known about isoform functions. A prior investigation of lncRNA RP11-369C8.1 reported that its splice variant TRMP suppressed p27 translation through PTBP1. Here we characterize a second major splice variant, TRMP-S (...

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Autores principales: Shuai, Tian, Khan, Muhammad Riaz, Zhang, Xu Dong, Li, Jingmin, Thorne, Rick Francis, Wu, Mian, Shao, Fengmin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141606/
https://www.ncbi.nlm.nih.gov/pubmed/34094715
http://dx.doi.org/10.1016/j.omtn.2021.04.004
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author Shuai, Tian
Khan, Muhammad Riaz
Zhang, Xu Dong
Li, Jingmin
Thorne, Rick Francis
Wu, Mian
Shao, Fengmin
author_facet Shuai, Tian
Khan, Muhammad Riaz
Zhang, Xu Dong
Li, Jingmin
Thorne, Rick Francis
Wu, Mian
Shao, Fengmin
author_sort Shuai, Tian
collection PubMed
description Long noncoding RNAs (lncRNAs) undergo extensive alternative splicing, but little is known about isoform functions. A prior investigation of lncRNA RP11-369C8.1 reported that its splice variant TRMP suppressed p27 translation through PTBP1. Here we characterize a second major splice variant, TRMP-S (short variant), whose enforced loss promotes cancer cell-cycle arrest and p27-dependent entry into cellular senescence. Remarkably, despite sharing a single common exon with TRMP, TRMP-S restrains p27 expression through distinct mechanisms. First, TRMP-S stabilizes UHRF1 protein levels, an epigenetic inhibitor of p27, by promoting interactions between UHRF1 and its deubiquitinating enzyme USP7. Alternatively, binding interactions between TRMP-S and FUBP3 prevent p53 mRNA interactions with RPL26 ribosomal protein, the latter essential for promoting p53 translation with ensuing suppression of p53 translation limiting p27 expression. Significantly, as TRMP-S is itself transactivated by p53, this identifies negative feedback regulation between p53 and TRMP-S. Different splicing variants of the RP11-369C8.1 gene thereby exert distinct roles that converge on the homeostatic control of p27 expression, providing an important precedent for understanding the actions of alternatively spliced lncRNAs.
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spelling pubmed-81416062021-06-03 lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence Shuai, Tian Khan, Muhammad Riaz Zhang, Xu Dong Li, Jingmin Thorne, Rick Francis Wu, Mian Shao, Fengmin Mol Ther Nucleic Acids Original Article Long noncoding RNAs (lncRNAs) undergo extensive alternative splicing, but little is known about isoform functions. A prior investigation of lncRNA RP11-369C8.1 reported that its splice variant TRMP suppressed p27 translation through PTBP1. Here we characterize a second major splice variant, TRMP-S (short variant), whose enforced loss promotes cancer cell-cycle arrest and p27-dependent entry into cellular senescence. Remarkably, despite sharing a single common exon with TRMP, TRMP-S restrains p27 expression through distinct mechanisms. First, TRMP-S stabilizes UHRF1 protein levels, an epigenetic inhibitor of p27, by promoting interactions between UHRF1 and its deubiquitinating enzyme USP7. Alternatively, binding interactions between TRMP-S and FUBP3 prevent p53 mRNA interactions with RPL26 ribosomal protein, the latter essential for promoting p53 translation with ensuing suppression of p53 translation limiting p27 expression. Significantly, as TRMP-S is itself transactivated by p53, this identifies negative feedback regulation between p53 and TRMP-S. Different splicing variants of the RP11-369C8.1 gene thereby exert distinct roles that converge on the homeostatic control of p27 expression, providing an important precedent for understanding the actions of alternatively spliced lncRNAs. American Society of Gene & Cell Therapy 2021-04-09 /pmc/articles/PMC8141606/ /pubmed/34094715 http://dx.doi.org/10.1016/j.omtn.2021.04.004 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Shuai, Tian
Khan, Muhammad Riaz
Zhang, Xu Dong
Li, Jingmin
Thorne, Rick Francis
Wu, Mian
Shao, Fengmin
lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence
title lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence
title_full lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence
title_fullStr lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence
title_full_unstemmed lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence
title_short lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence
title_sort lncrna trmp-s directs dual mechanisms to regulate p27-mediated cellular senescence
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141606/
https://www.ncbi.nlm.nih.gov/pubmed/34094715
http://dx.doi.org/10.1016/j.omtn.2021.04.004
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