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Novel SLCO2B1 mRNA isoform acts as a noncoding RNA and drives cancer progression through FMR1-mediated protein biosynthesis

ABSTRACT: The eukaryotic 5’ untranslated region (5’ UTR) canonically influences mRNA translation efficiency. However, the role of the 5’ UTR structure in blocking mRNA translation and turning a coding RNA into a noncoding RNA remains undocumented. Herein, we discovered a novel mRNA isoform of the human solute carrier organic anion transporter family member 2B1 (SLCO2B1) gene, named SLCO2B1-isoformNovel (SLCO2B1-isoN), whose 5’ end stem‒loop abrogates its translational capacity and turns it into a noncoding RNA. The SLCO2B1-isoN noncoding isoform stabilizes fragile X messenger ribonucleoprotein 1 (FMR1) to trigger hepatocellular carcinoma (HCC) progression by facilitating de novo protein biosynthesis. Targeting SLCO2B1-isoN effectively inhibited orthotopic tumor xenograft growth in vivo. In conclusion, this study revealed a previously unrecognized noncoding isoform of SLCO2B1 mRNA with a 5’ end stem‒loop structure and highlighted the dual characteristics of mRNAs harboring protein-coding and noncoding isoforms, providing new insights into the richness of genetic information in protein-coding genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312581 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:Translation of mRNA into a polypeptide is terminated when the release factor eRF1 recognizes a UAA, UAG, or UGA stop codon in the ribosomal A site and stimulates nascent peptide release. However, stop codon readthrough can occur when a near-cognate tRNA outcompetes eRF1 in decoding the stop codon, resulting in the continuation of the elongation phase of protein synthesis. At the end of a conventional mRNA coding region readthrough allows translation into the mRNA 3’-UTR. Previous studies with reporter systems have shown that the efficiency of termination or readthrough is modulated by cis-acting elements other than stop codon identity, including two nucleotides 5’ of the stop codon, six nucleotides 3’ of the stop codon in the ribosomal mRNA channel, and stem-loop structures in the mRNA 3’-UTR. It is unknown whether these elements are important at a genome-wide level and whether other mRNA features proximal to the stop codon significantly affect termination and readthrough efficiencies in vivo. Accordingly, we carried out ribosome profiling analyses of yeast cells expressing wild-type or temperature-sensitive eRF1 and developed bioinformatics strategies to calculate readthrough efficiency, and to identify mRNA and peptide features which influence that efficiency. We found that the stop codon (nt +1 to +3), the nucleotide after it (nt +4), the codon in the P site (nt -3 to -1), and 3’-UTR length are the most influential features in the control of readthrough efficiency, while nts +5 to +9 and mRNA secondary structure in the 3’-UTR had milder effects. Additionally, we found low readthrough genes to have shorter 3’-UTRs compared to high readthrough genes in cells with thermally inactivated eRF1, while this trend was reversed in wild-type cells. Together, our results demonstrated the general roles of known regulatory elements in genome-wide regulation and identified several new mRNA or peptide features important for translation termination and readthrough.

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Novel SLCO2B1 mRNA isoform acts as a noncoding RNA and drives cancer progression through FMR1-mediated protein biosynthesis

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