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 (...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Molecular therapy. Nucleic acids 2021-06, Vol.24, p.971-985
Hauptverfasser: Shuai, Tian, Khan, Muhammad Riaz, Zhang, Xu Dong, Li, Jingmin, Thorne, Rick Francis, Wu, Mian, Shao, Fengmin
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. [Display omitted] 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.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2021.04.004