lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence
| العنوان: | lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence |
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| المؤلفون: | Fengmin Shao, Tian Shuai, Rick F. Thorne, Mian Wu, Muhammad Riaz Khan, Jingmin Li, Xudong Zhang |
| المصدر: | Molecular Therapy: Nucleic Acids, Vol 24, Iss, Pp 971-985 (2021) Molecular Therapy. Nucleic Acids |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, p53, senescence, RM1-950, Deubiquitinating enzyme, 03 medical and health sciences, Exon, alternative splicing, 0302 clinical medicine, Drug Discovery, Epigenetics, UHRF1, RP11-369C8.1, Gene, biology, p21, TRMP-S, Alternative splicing, Translation (biology), PTBP1, Cell biology, 030104 developmental biology, lncRNA isoform, 030220 oncology & carcinogenesis, RNA splicing, biology.protein, Molecular Medicine, Original Article, Therapeutics. Pharmacology, FUBP3, RPL26 |
| الوصف: | 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. Graphical abstract Akin to coding genes, lncRNAs undergo extensive splicing, but there are limited reports detailing functional outcomes. Shuai et al. reveal that TRMP-S, a variant transcript of the RP11-369C8.1 gene, functions through dual epigenetic and transcriptional mechanisms to inhibit p27 expression, restraining cancer cell-cycle arrest and entry into cellular senescence. |
| اللغة: | English |
| تدمد: | 2162-2531 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e3d1d4079b44cdbe79c4344ef060b448Test http://www.sciencedirect.com/science/article/pii/S2162253121000986Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e3d1d4079b44cdbe79c4344ef060b448 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21622531 |
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