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Splicing-accessible coding 3'UTRs control protein stability and interaction networks

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Item Type:Article
Title:Splicing-accessible coding 3'UTRs control protein stability and interaction networks
Creators Name:Preussner, M. and Gao, Q. and Morrison, E. and Herdt, O. and Finkernagel, F. and Schumann, M. and Krause, E. and Freund, C. and Chen, W. and Heyd, F.
Abstract:BACKGROUND: 3'-Untranslated regions (3'UTRs) play crucial roles in mRNA metabolism, such as by controlling mRNA stability, translation efficiency, and localization. Intriguingly, in some genes the 3'UTR is longer than their coding regions, pointing to additional, unknown functions. Here, we describe a protein-coding function of 3'UTRs upon frameshift-inducing alternative splicing in more than 10% of human and mouse protein-coding genes. RESULTS: 3'UTR-encoded amino acid sequences show an enrichment of PxxP motifs and lead to interactome rewiring. Furthermore, an elevated proline content increases protein disorder and reduces protein stability, thus allowing splicing-controlled regulation of protein half-life. This could also act as a surveillance mechanism for erroneous skipping of penultimate exons resulting in transcripts that escape nonsense mediated decay. The impact of frameshift-inducing alternative splicing on disease development is emphasized by a retinitis pigmentosa-causing mutation leading to translation of a 3'UTR-encoded, proline-rich, destabilized frameshift-protein with altered protein-protein interactions. CONCLUSIONS: We describe a widespread, evolutionarily conserved mechanism that enriches the mammalian proteome, controls protein expression and protein-protein interactions, and has important implications for the discovery of novel, potentially disease-relevant protein variants.
Keywords:Alternative Splicing, 3'UTR, Protein Stability, Protein Disorder, Protein-Protein Interaction, Alternative Open Reading Frame, Genome Structure, Animals, Mice
Source:Genome Biology
Publisher:BioMed Central
Page Range:186
Date:29 July 2020
Official Publication:https://doi.org/10.1186/s13059-020-02102-3
PubMed:View item in PubMed

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