Dynamic modulation of Dnmt2-dependent tRNA methylation by the micronutrient queuine

Müller, Martin; Hartmann, Mark; Schuster, Isabelle; Bender, Sebastian; Thüring, Kathrin; Helm, Mark; Katze, Jon R.; Nellen, Wolfgang; Lyko, Frank; Ehrenhofer‐Murray, Ann E.

doi:10.1093/nar/gkv980

Cited by 78 publications

(96 citation statements)

References 51 publications

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“…In cells grown in standard complete or minimal medium, tRNA Asp methylation as measured by RNA bisulfite sequencing was found to be rather low (approx. 14%–20% [10,12]). However, overexpression of the pmt1 + gene under an inducible promoter yields 100% tRNA Asp methylation, and tRNA Glu methylation is marginally increased, indicating that Dnmt2 levels in wild-type (wt) cells are limiting for in vivo tRNA methylation.…”

Section: Trna Methylation By the Dnmt2 Family Of Rna Methyltransfementioning

confidence: 99%

“…As kind of a “shot in the dark”, we therefore hypothesized that queuine might be the agent that, when introduced at G34 of tRNA Asp , stimulates Dnmt2-dependent tRNA methylation. Lo and behold, cultivating S. pombe in the presence of queuine resulted in an increase of in vivo tRNA Asp methylation to 100% [12]. This revealed an unanticipated link between queuine modification and Dnmt2-dependent C38 methylation (Figure 1).…”

Section: Trna Methylation By the Dnmt2 Family Of Rna Methyltransfementioning

confidence: 99%

“…Our investigation of Dnmt2-dependent m 5 C38 methylation of tRNA Asp led us to discover an unexpected link between queuosine modification and methylation [12]. We found increased activity of Dnmt2/Pmt1 on tRNA isolated ex vivo that was Q-modified as compared to non-Q-containing tRNA.…”

Section: Molecular Consequences Of Queuosine Modification and Dnmtmentioning

confidence: 99%

“…Our discovery of a Q-mediated mechanism of C38 methylation by Dnmt2 in S. pombe [12] begs the question whether Dnmt2 homologs from other organisms are also sensitive to prior Q incorporation. Our use of S. pombe as a model system was fortunate, because media conditions can be easily be manipulated, which allowed us to discover this unexpected link.…”

Section: Molecular Consequences Of Queuosine Modification and Dnmtmentioning

confidence: 99%

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Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification

Ehrenhofer‐Murray

2017

Biomolecules

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Enzymes of the Dnmt2 family of methyltransferases have yielded a number of unexpected discoveries. The first surprise came more than ten years ago when it was realized that, rather than being DNA methyltransferases, Dnmt2 enzymes actually are transfer RNA (tRNA) methyltransferases for cytosine-5 methylation, foremost C38 (m5C38) of tRNAAsp. The second unanticipated finding was our recent discovery of a nutritional regulation of Dnmt2 in the fission yeast Schizosaccharomyces pombe. Significantly, the presence of the nucleotide queuosine in tRNAAsp strongly stimulates Dnmt2 activity both in vivo and in vitro in S. pombe. Queuine, the respective base, is a hypermodified guanine analog that is synthesized from guanosine-5’-triphosphate (GTP) by bacteria. Interestingly, most eukaryotes have queuosine in their tRNA. However, they cannot synthesize it themselves, but rather salvage it from food or from gut microbes. The queuine obtained from these sources comes from the breakdown of tRNAs, where the queuine ultimately was synthesized by bacteria. Queuine thus has been termed a micronutrient. This review summarizes the current knowledge of Dnmt2 methylation and queuosine modification with respect to translation as well as the organismal consequences of the absence of these modifications. Models for the functional cooperation between these modifications and its wider implications are discussed.

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Section: Trna Methylation By the Dnmt2 Family Of Rna Methyltransfementioning

confidence: 99%

Section: Trna Methylation By the Dnmt2 Family Of Rna Methyltransfementioning

confidence: 99%

Section: Molecular Consequences Of Queuosine Modification and Dnmtmentioning

confidence: 99%

Section: Molecular Consequences Of Queuosine Modification and Dnmtmentioning

confidence: 99%

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Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification

Ehrenhofer‐Murray

2017

Biomolecules

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“…Interestingly, it has also been shown that C38 tRNA methylation in Schizosaccharomyces pombe is regulated by queuine [87]. As 5mC at C38 has been shown to have a function in translational accuracy [84], these results suggest a novel and exciting mechanism that allows nutritional factors to modulate mRNA decoding and translation.…”

Section: Genome Recoding By Trna Modificationsmentioning

confidence: 99%

Genome recoding by tRNA modifications

Tuorto¹,

Lyko²

2016

Open Biol.

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RNA modifications are emerging as an additional regulatory layer on top of the primary RNA sequence. These modifications are particularly enriched in tRNAs where they can regulate not only global protein translation, but also protein translation at the codon level. Modifications located in or in the vicinity of tRNA anticodons are highly conserved in eukaryotes and have been identified as potential regulators of mRNA decoding. Recent studies have provided novel insights into how these modifications orchestrate the speed and fidelity of translation to ensure proper protein homeostasis. This review highlights the prominent modifications in the tRNA anticodon loop: queuosine, inosine, 5-methoxycarbonylmethyl-2-thiouridine, wybutosine, threonyl–carbamoyl–adenosine and 5-methylcytosine. We discuss the functional relevance of these modifications in protein translation and their emerging role in eukaryotic genome recoding during cellular adaptation and disease.

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Functional interplay within the epitranscriptome: Reality or fiction?

2021

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RNA modifications have recently emerged as an important regulatory layer of gene expression. The most prevalent and reversible modification on messenger RNA (mRNA), N6‐methyladenosine, regulates most steps of RNA metabolism and its dysregulation has been associated with numerous diseases. Other modifications such as 5‐methylcytosine and N1‐methyladenosine have also been detected on mRNA but their abundance is lower and still debated. Adenosine to inosine RNA editing is widespread on coding and non‐coding RNA and can alter mRNA decoding as well as protect against autoimmune diseases. 2′‐O‐methylation of the ribose and pseudouridine are widespread on ribosomal and transfer RNA and contribute to proper RNA folding and stability. While the understanding of the individual role of RNA modifications has now reached an unprecedented stage, still little is known about their interplay in the control of gene expression. In this review we discuss the examples where such interplay has been observed and speculate that with the progress of mapping technologies more of those will rapidly accumulate.

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Dynamic modulation of Dnmt2-dependent tRNA methylation by the micronutrient queuine

Cited by 78 publications

References 51 publications

Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification

Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification

Genome recoding by tRNA modifications

Functional interplay within the epitranscriptome: Reality or fiction?

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