Sebastian Kirchner, Zhiwei Cai, Robert Rauscher, Nicolai Kastelic, Melanie Anding, Andreas Czech, Bertrand Kleizen, Lynda S. Ostedgaard, Ineke Braakman, David N. Sheppard, Zoya Ignatova
- Synonymous single nucleotide polymorphisms (sSNPs) are considered neutral for protein function, as by definition they exchange only codons, not amino acids. We identified an sSNP that modifies the local translation speed of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to detrimental changes to protein stability and function. This sSNP introduces a codon pairing to a low-abundance tRNA that is particularly rare in human bronchial epithelia, but not in other human tissues, suggesting tissue-specific effects of this sSNP. Up-regulation of the tRNA cognate to the mutated codon counteracts the effects of the sSNP and rescues protein conformation and function. Our results highlight the wide-ranging impact of sSNPs, which invert the programmed local speed of mRNA translation and provide direct evidence for the central role of cellular tRNA levels in mediating the actions of sSNPs in a tissue-specific manner.
MetadatenVerfasserangaben: | Sebastian Kirchner, Zhiwei Cai, Robert Rauscher, Nicolai Kastelic, Melanie Anding, Andreas Czech, Bertrand Kleizen, Lynda S. Ostedgaard, Ineke BraakmanORCiD, David N. Sheppard, Zoya Ignatova |
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DOI: | https://doi.org/10.1371/journal.pbio.2000779 |
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ISSN: | 1545-7885 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/28510592 |
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Titel des übergeordneten Werks (Englisch): | PLoS biology |
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Verlag: | PLoS |
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Verlagsort: | San Fransisco |
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Publikationstyp: | Wissenschaftlicher Artikel |
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Sprache: | Englisch |
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Jahr der Erstveröffentlichung: | 2017 |
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Erscheinungsjahr: | 2017 |
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Datum der Freischaltung: | 20.04.2020 |
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Band: | 15 |
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Seitenanzahl: | 29 |
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Fördernde Institution: | CF Trust [PJ554, SRC 005]; CF Foundation [BRAAKM08XX0, BRAAKM14XX0, SHEPPA14XX0]; NIH [HL091842, HL51670]; CF Foundation, Research Development program [OSTEDG1410]; University of Pittsburgh Cancer Institute (UPCI) Health Sciences Tissue bank [P30CA047904]; DFG [SFB 740, FOR 1805]; Mukoviscidose e.V. [1603] |
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Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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Peer Review: | Referiert |
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