- Title
- lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence
- Creator
- Shuai, Tian; Khan, Muhammad Riaz; Zhang, Xu Dong; Li, Jingmin; Thorne, Rick Francis; Wu, Mian; Shao, Fengmin
- Relation
- NHMRC.1147271 http://purl.org/au-research/grants/nhmrc/1147271
- Relation
- Molecular Therapy - Nucleic Acids Vol. 24, p. 971-985
- Publisher Link
- http://dx.doi.org/10.1016/j.omtn.2021.04.004
- Publisher
- Cell Press
- Resource Type
- journal article
- Date
- 2021
- 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.
- Subject
- alternative splicing; FUBP3; SDG 3; Sustainable Development Goals; lncRNA isoform; p53; p21; RP11-369C8.1; RPL26; senescence; TRMP-S; UHRF1
- Identifier
- http://hdl.handle.net/1959.13/1465230
- Identifier
- uon:47238
- Identifier
- ISSN:2162-2531
- Rights
- © 2021 The Authors
- Language
- eng
- Full Text
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