Splicing-accessible coding 3′UTRs control protein stability and interaction networks
| Autor: | Florian Heyd, Wei Chen, Eberhard Krause, Marco Preussner, Christian Freund, Qingsong Gao, Eliot Morrison, Michael Schümann, Florian Finkernagel, Olga Herdt |
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| Rok vydání: | 2020 |
| Předmět: |
lcsh:QH426-470
Nonsense-mediated decay Computational biology Biology 3′UTR Interactome 500 Naturwissenschaften und Mathematik::570 Biowissenschaften Biologie::576 Genetik und Evolution Mice Exon Protein-protein interaction Genome structure Protein stability Animals Humans Coding region 3' Untranslated Regions lcsh:QH301-705.5 Gene Cyclic Nucleotide Phosphodiesterases Type 6 Three prime untranslated region Research Alternative splicing lcsh:Genetics lcsh:Biology (General) RNA splicing RNA Splice Sites Protein disorder Technology Platforms Alternative open reading frame |
| Zdroj: | Genome Biology, Vol 21, Iss 1, Pp 1-24 (2020) Genome Biology |
| DOI: | 10.17169/refubium-30159 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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