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

Tian Shuai; Muhammad Riaz Khan; Xu Dong Zhang; Jingmin Li; Rick Francis Thorne; Mian Wu; Fengmin Shao

doi:10.1016/j.omtn.2021.04.004

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

Mol Ther Nucleic Acids. 2021 Apr 9:24:971-985. doi: 10.1016/j.omtn.2021.04.004. eCollection 2021 Jun 4.

Authors

Tian Shuai¹, Muhammad Riaz Khan¹, Xu Dong Zhang^{1

2}, Jingmin Li¹, Rick Francis Thorne^{1

3}, Mian Wu^{1

4}, Fengmin Shao¹

Affiliations

¹ Translational Research Institute, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, China.
² School of Biomedical Sciences & Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia.
³ School of Environmental & Life Sciences, The University of Newcastle, Callaghan, NSW 2258, Australia.
⁴ CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Centre for Excellence in Molecular Cell Science, the First Affiliated Hospital of University of Science and Technology of China, Hefei 230027, China.

Abstract

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.

Keywords: FUBP3; RP11-369C8.1; RPL26; TRMP-S; UHRF1; alternative splicing; lncRNA isoform; p21; p53; senescence.