Riley, J.J. orcid.org/0000-0002-0311-7787, Alexandru-Crivac, C.N., Bryce-Smith, S. et al. (2 more authors) (2025) Widespread 3′ UTR splicing regulates expression of oncogene transcripts through multiple mechanisms. Nucleic Acids Research, 53 (14). gkaf700. gkaf700. ISSN: 0305-1048
Abstract
Splicing in 3′ untranslated regions (3′ UTRs) is generally expected to elicit degradation via nonsense-mediated decay (NMD) due to the presence of an exon junction complex (EJC) downstream of the stop codon. However, 3′ UTR intron (3UI)-containing transcripts are widespread and highly expressed in both normal tissues and cancers. We present a transcriptome assembly built from 7897 solid tumour and normal samples from The Cancer Genome Atlas. We identify thousands of 3UI-containing transcripts, many expressed across multiple cancer types. Expression of NMD component UPF1 negatively correlates with 3UI-splicing in normal, but not colon cancer, samples. 3UIs found exclusively within 3′ UTRs (bona-fide 3UIs) are not predominantly NMD-sensitizing, unlike introns found in 3′ UTRs due to the presence of an early premature termination codon (PTC). We identify 3UI-splicing that rescues the transcript from NMD. Bona-fide 3UI-transcripts are over-spliced in cancer samples. In colon cancer, differentially-spliced 3UI transcripts are enriched in the Wnt signalling pathway, with CTNNB1 showing the greatest increase in splicing. Manipulating Wnt signalling can further regulate 3UI-splicing of Wnt components. Our results indicate that 3′ UTR splicing is not a rare occurrence and 3UI-splicing can regulate transcript expression in multiple ways, some of which are likely to be EJC-independent.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2025. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Biological Sciences; Bioinformatics and Computational Biology; Human Genome; Digestive Diseases; Genetics; Colo-Rectal Cancer; Cancer Genomics; Cancer; Cancer |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Funding Information: | Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/R007268/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 06 Aug 2025 14:39 |
Last Modified: | 06 Aug 2025 14:39 |
Status: | Published |
Publisher: | Oxford University Press (OUP) |
Refereed: | Yes |
Identification Number: | 10.1093/nar/gkaf700 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:230141 |