A common tRNA modification at an unusual location: the discovery of wyosine biosynthesis in mitochondria

Sample, Paul; Kořený, Luděk; Paris, Zdeněk; Gaston, Kirk W.; Rubio, Mary Anne T.; Fleming, Ian M.C.; Hinger, Scott A.; Horáková, Eva; Limbach, Patrick A.; Lukeš, J; Alfonzo, Juan D.

doi:10.1093/nar/gkv286

Cited by 24 publications

(26 citation statements)

References 41 publications

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“…In the cycloheximide growth curve, a concentration of the drug was used that is non-inhibitory to wild-type cells. Targeted gene downregulation was confirmed by RT–PCR, as described elsewhere 23 .…”

Section: Methodsmentioning

confidence: 99%

Editing and methylation at a single site by functionally interdependent activities

Rubio

Gaston

McKenney

et al. 2017

Nature

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Nucleic acids undergo naturally occurring chemical modifications. Over 100 different modifications have been described and every position in the purine and pyrimidine bases can be modified; often the sugar is also modified1. Despite recent progress, the mechanism for the biosynthesis of most modifications is not fully understood, owing, in part, to the difficulty associated with reconstituting enzyme activity in vitro. Whereas some modifications can be efficiently formed with purified components, others may require more intricate pathways2. A model for modification interdependence, in which one modification is a prerequisite for another, potentially explains a major hindrance in reconstituting enzymatic activity in vitro3. This model was prompted by the earlier discovery of tRNA cytosine-to-uridine editing in eukaryotes, a reaction that has not been recapitulated in vitro and the mechanism of which remains unknown. Here we show that cytosine 32 in the anticodon loop of Trypanosoma brucei tRNAThr is methylated to 3-methylcytosine (m3C) as a pre-requisite for C-to-U deamination. Formation of m3C in vitro requires the presence of both the T. brucei m3C methyltransferase TRM140 and the deaminase ADAT2/3. Once formed, m3C is deaminated to 3-methyluridine (m3U) by the same set of enzymes. ADAT2/3 is a highly mutagenic enzyme4, but we also show that when co-expressed with the methyltransferase its mutagenicity is kept in check. This helps to explain how T. brucei escapes ‘wholesale deamination’5 of its genome while harbouring both enzymes in the nucleus. This observation has implications for the control of another mutagenic deaminase, human AID, and provides a rationale for its regulation.

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Section: Methodsmentioning

confidence: 99%

Editing and methylation at a single site by functionally interdependent activities

Rubio

Gaston

McKenney

et al. 2017

Nature

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“…Still, tRNA Phe G 37 is extensively modified. The G 37 of tRNA Phe from Archaea, Eukarya and even mitochondria is modified to a tricyclic wyosine/wybutosine, imG/yW, (3H-Imidazo[1,2-α]purine-7-butanoic acid, 4,9-dihydro-α-[(methoxycarbonyl)amino]-4,6-dimethyl-9-oxo-3-β-D-ribofuranosyl-, methyl ester, (αS)-) or a derivative [186,187], the biosynthesis of which begins with a simple N1 methylation [188].…”

Section: Modifications At Position 37mentioning

confidence: 99%

Chemical and Conformational Diversity of Modified Nucleosides Affects tRNA Structure and Function

et al. 2017

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RNAs are central to all gene expression through the control of protein synthesis. Four major nucleosides, adenosine, guanosine, cytidine and uridine, compose RNAs and provide sequence variation, but are limited in contributions to structural variation as well as distinct chemical properties. The ability of RNAs to play multiple roles in cellular metabolism is made possible by extensive variation in length, conformational dynamics, and the over 100 post-transcriptional modifications. There are several reviews of the biochemical pathways leading to RNA modification, but the physicochemical nature of modified nucleosides and how they facilitate RNA function is of keen interest, particularly with regard to the contributions of modified nucleosides. Transfer RNAs (tRNAs) are the most extensively modified RNAs. The diversity of modifications provide versatility to the chemical and structural environments. The added chemistry, conformation and dynamics of modified nucleosides occurring at the termini of stems in tRNA’s cloverleaf secondary structure affect the global three-dimensional conformation, produce unique recognition determinants for macromolecules to recognize tRNAs, and affect the accurate and efficient decoding ability of tRNAs. This review will discuss the impact of specific chemical moieties on the structure, stability, electrochemical properties, and function of tRNAs.

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“…However, recently wyosine and its derivatives were found in mitochondria of trypanosomatids. [96] This was unexpected since it was generally assumed that mitochondrial tRNA modifications would resemble more the bacterial pattern due to their close evolutionary relationship. Probably these complex wyosine derivatives at position 37 are beneficial for maintaining the reading frame in mitochondrial translation in the light of the U-rich nature of mRNA codons in trypanosomal mitochondria that result from the immense U insertion mRNA editing mechanism.…”

Section: Functions Of Trna Modificationsmentioning

confidence: 99%

tRNA Biology in Trypanosomes

Shikha¹,

Brogli²,

Schneider³

et al. 2019

Chimia

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Besides their medical importance, the parasitic protozoan Trypanosoma brucei and its relatives are experimentally highly accessible model systems for many cell biological processes. Trypanosomes are phylogenetically essentially unrelated to the popular model eukaryotes, such as yeast and animals, and thus show several unique features, many of which are connected to RNA. Here we review the tRNA biology of trypanosomes. Even though tRNAs were already discovered 60 years ago, owing to current technological advances in the field, research on tRNA biology has seen a Renaissance in recent years. First we discuss the extensive mitochondrial tRNA import process and the consequences it has for the parasite. Next we focus on trypanosomal aminoacyl-tRNA synthetases, some of which may be exploited as drug targets. Furthermore, we summarize what is known about trypanosomal tRNA modifications in both the cytosol and the mitochondrion. Finally, we provide an overview on the emerging field of tRNA-derived fragments and their possible function as translation regulators.

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A common tRNA modification at an unusual location: the discovery of wyosine biosynthesis in mitochondria

Cited by 24 publications

References 41 publications

Editing and methylation at a single site by functionally interdependent activities

Editing and methylation at a single site by functionally interdependent activities

Chemical and Conformational Diversity of Modified Nucleosides Affects tRNA Structure and Function

tRNA Biology in Trypanosomes

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