Queuosine‐modified tRNAs confer nutritional control of protein translation |
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Authors: | Francesca Tuorto Carine Legrand Cansu Cirzi Giuseppina Federico Reinhard Liebers Martin Müller Ann E Ehrenhofer‐Murray Gunnar Dittmar Hermann‐Josef Gröne Frank Lyko |
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Affiliation: | 1. Division of Epigenetics, DKFZ‐ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany;2. Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany;3. Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany;4. Institut für Biologie, Humboldt‐Universit?t zu Berlin, Berlin, Germany;5. Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg |
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Abstract: | Global protein translation as well as translation at the codon level can be regulated by tRNA modifications. In eukaryotes, levels of tRNA queuosinylation reflect the bioavailability of the precursor queuine, which is salvaged from the diet and gut microbiota. We show here that nutritionally determined Q‐tRNA levels promote Dnmt2‐mediated methylation of tRNA Asp and control translational speed of Q‐decoded codons as well as at near‐cognate codons. Deregulation of translation upon queuine depletion results in unfolded proteins that trigger endoplasmic reticulum stress and activation of the unfolded protein response, both in cultured human cell lines and in germ‐free mice fed with a queuosine‐deficient diet. Taken together, our findings comprehensively resolve the role of this anticodon tRNA modification in the context of native protein translation and describe a novel mechanism that links nutritionally determined modification levels to effective polypeptide synthesis and cellular homeostasis. |
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Keywords: | cytosine‐5 methylation protein translation queuosine tRNA modifications unfolded protein response |
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