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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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253121000986 |
| _version_ | 1818907085787627520 |
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| author | Tian Shuai Muhammad Riaz Khan Xu Dong Zhang Jingmin Li Rick Francis Thorne Mian Wu Fengmin Shao |
| author_facet | Tian Shuai Muhammad Riaz Khan Xu Dong Zhang Jingmin Li Rick Francis Thorne Mian Wu Fengmin Shao |
| author_sort | Tian Shuai |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T21:49:31Z |
| format | Article |
| id | doaj.art-bd46f200ed3b410eb3724568c2bb1f9d |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-19T21:49:31Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-bd46f200ed3b410eb3724568c2bb1f9d2022-12-21T20:04:27ZengElsevierMolecular Therapy: Nucleic Acids2162-25312021-06-0124971985lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescenceTian Shuai0Muhammad Riaz Khan1Xu Dong Zhang2Jingmin Li3Rick Francis Thorne4Mian Wu5Fengmin Shao6Translational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, ChinaTranslational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, ChinaTranslational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, China; School of Biomedical Sciences & Pharmacy, The University of Newcastle, Callaghan, NSW 2308, AustraliaTranslational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, ChinaTranslational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, China; School of Environmental & Life Sciences, The University of Newcastle, Callaghan, NSW 2258, Australia; Corresponding author: Rick Francis Thorne, Translational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, China.Translational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, China; 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; Corresponding author: Mian Wu, Translational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, China.Translational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, China; Corresponding author: Fengmin Shao, Translational Research Institute, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, Zhengzhou 450003, China.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.http://www.sciencedirect.com/science/article/pii/S2162253121000986alternative splicingFUBP3lncRNA isoformp53p21RP11-369C8.1 |
| spellingShingle | Tian Shuai Muhammad Riaz Khan Xu Dong Zhang Jingmin Li Rick Francis Thorne Mian Wu Fengmin Shao lncRNA TRMP-S directs dual mechanisms to regulate p27-mediated cellular senescence Molecular Therapy: Nucleic Acids alternative splicing FUBP3 lncRNA isoform p53 p21 RP11-369C8.1 |
| 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 | alternative splicing FUBP3 lncRNA isoform p53 p21 RP11-369C8.1 |
| url | http://www.sciencedirect.com/science/article/pii/S2162253121000986 |
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