tRNA wobble modifications and protein homeostasis

Ranjan, Namit; Rodnina, Marina V.

doi:10.1080/21690731.2016.1143076

Cited by 59 publications

(51 citation statements)

References 76 publications

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“…The large majority of rRNA modifications are already installed co‐transcriptionally by small nucleolar (sno)RNPs, and only few base modifications require the action of lone‐standing enzymes (Watkins & Bohnsack, 2012; Sharma & Lafontaine, 2015). tRNAs contain the largest variety of nucleoside modifications, and many of them are suggested to affect tRNA biogenesis and nuclear export, tRNA structure, interaction with aminoacyl‐tRNA‐sythetases or codon recognition during translation (Agris et al , 2007; Leisegang et al , 2012; Hori, 2014; Duechler et al , 2016; Ranjan & Rodnina, 2016). Many tRNAs contain base modifications of the nucleoside at position 34 of the tRNA anticodon (the “wobble position”).…”

Section: Introductionmentioning

confidence: 99%

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

et al. 2016

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Mitochondrial gene expression uses a non‐universal genetic code in mammals. Besides reading the conventional AUG codon, mitochondrial (mt‐)tRNAM et mediates incorporation of methionine on AUA and AUU codons during translation initiation and on AUA codons during elongation. We show that the RNA methyltransferase NSUN3 localises to mitochondria and interacts with mt‐tRNAM et to methylate cytosine 34 (C34) at the wobble position. NSUN3 specifically recognises the anticodon stem loop (ASL) of the tRNA, explaining why a mutation that compromises ASL basepairing leads to disease. We further identify ALKBH1/ABH1 as the dioxygenase responsible for oxidising m5C34 of mt‐tRNAM et to generate an f5C34 modification. In vitro codon recognition studies with mitochondrial translation factors reveal preferential utilisation of m5C34 mt‐tRNA Met in initiation. Depletion of either NSUN3 or ABH1 strongly affects mitochondrial translation in human cells, implying that modifications generated by both enzymes are necessary for mt‐tRNAM et function. Together, our data reveal how modifications in mt‐tRNAM et are generated by the sequential action of NSUN3 and ABH1, allowing the single mitochondrial tRNAM et to recognise the different codons encoding methionine.

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Section: Introductionmentioning

confidence: 99%

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

et al. 2016

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“…Modifications occurring at or near the anticodon loop, in particular at positions 34 and 37, are highly conserved in eukaryotes and affect specific codon–anticodon interactions, regulating translational efficiency and fidelity. In fact, the vast majority of tRNA modifications occur at the wobble position (position 34), ensuring the correct codon–anticodon base pairing and reading frame maintenance while preventing translational frameshifting [9]. Modifications at this position are generally associated with decoding by increasing the diversity of codon recognition through codon–anticodon wobbling.…”

Section: Introductionmentioning

confidence: 99%

Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

Pereira

Francisco

Varanda

et al. 2018

IJMS

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Transfer RNAs (tRNAs) are key players of protein synthesis, as they decode the genetic information organized in mRNA codons, translating them into the code of 20 amino acids. To be fully active, tRNAs undergo extensive post-transcriptional modifications, catalyzed by different tRNA-modifying enzymes. Lack of these modifications increases the level of missense errors and affects codon decoding rate, contributing to protein aggregation with deleterious consequences to the cell. Recent works show that tRNA hypomodification and tRNA-modifying-enzyme deregulation occur in several diseases where proteostasis is affected, namely, neurodegenerative and metabolic diseases. In this review, we discuss the recent findings that correlate aberrant tRNA modification with proteostasis imbalances, in particular in neurological and metabolic disorders, and highlight the association between tRNAs, their modifying enzymes, translational decoding, and disease onset.

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“…9,25-30 Each of the modified nucleosides contribute distinct chemistries, nucleoside conformations and dynamics, and their contributions to decoding have been studied extensively over decades and most recently reviewed. 20,22,24,28,31-38 However, there is significant evidence that a combination of two or three anticodon domain modifications play a synergistic role in tRNA function where modification of a wobble position U is crucial. 9,20,24,39-46 Today, we know that certain modifications of U 34 enable expansion of codon from NNA/G recognition to synonymous codons ending in pyrimidines, N1-N2-Pyr, where N is any of the 4 nucleosides and Pyr is either U or C. 29 Yet, the anticodon domain of some tRNA species lack modification and can be totally devoid of modified nucleosides.…”

Section: The Importance Of Being Modifiedmentioning

confidence: 99%

Celebrating wobble decoding: Half a century and still much is new

et al. 2017

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A simple post-transcriptional modification of tRNA, deamination of adenosine to inosine at the first, or wobble, position of the anticodon, inspired Francis Crick's Wobble Hypothesis 50 years ago. Many more naturally-occurring modifications have been elucidated and continue to be discovered. The post-transcriptional modifications of tRNA's anticodon domain are the most diverse and chemically complex of any RNA modifications. Their contribution with regards to chemistry, structure and dynamics reveal individual and combined effects on tRNA function in recognition of cognate and wobble codons. As forecast by the Modified Wobble Hypothesis 25 years ago, some individual modifications at tRNA's wobble position have evolved to restrict codon recognition whereas others expand the tRNA's ability to read as many as four synonymous codons. Here, we review tRNA wobble codon recognition using specific examples of simple and complex modification chemistries that alter tRNA function. Understanding natural modifications has inspired evolutionary insights and possible innovation in protein synthesis.

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tRNA wobble modifications and protein homeostasis

Cited by 59 publications

References 76 publications

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

Celebrating wobble decoding: Half a century and still much is new

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tRNA wobble modifications and protein homeostasis

Cited by 59 publications

References 76 publications

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA Met to expand codon recognition in mitochondrial translation

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA Met to expand codon recognition in mitochondrial translation

Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

Celebrating wobble decoding: Half a century and still much is new

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NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation