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Review
, 73 (16), 3075-95

Nucleoside Modifications in the Regulation of Gene Expression: Focus on tRNA

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Review

Nucleoside Modifications in the Regulation of Gene Expression: Focus on tRNA

Markus Duechler et al. Cell Mol Life Sci.

Abstract

Both, DNA and RNA nucleoside modifications contribute to the complex multi-level regulation of gene expression. Modified bases in tRNAs modulate protein translation rates in a highly dynamic manner. Synonymous codons, which differ by the third nucleoside in the triplet but code for the same amino acid, may be utilized at different rates according to codon-anticodon affinity. Nucleoside modifications in the tRNA anticodon loop can favor the interaction with selected codons by stabilizing specific base pairs. Similarly, weakening of base pairing can discriminate against binding to near-cognate codons. mRNAs enriched in favored codons are translated in higher rates constituting a fine-tuning mechanism for protein synthesis. This so-called codon bias establishes a basic protein level, but sometimes it is necessary to further adjust the production rate of a particular protein to actual requirements, brought by, e.g., stages in circadian rhythms, cell cycle progression or exposure to stress. Such an adjustment is realized by the dynamic change of tRNA modifications resulting in the preferential translation of mRNAs coding for example for stress proteins to facilitate cell survival. Furthermore, tRNAs contribute in an entirely different way to another, less specific stress response consisting in modification-dependent tRNA cleavage that contributes to the general down-regulation of protein synthesis. In this review, we summarize control functions of nucleoside modifications in gene regulation with a focus on recent findings on protein synthesis control by tRNA base modifications.

Keywords: Modified nucleosides; Regulation of gene expression; Stress signaling; Translation rate; tRNA.

Figures

Fig. 1
Fig. 1
Functional diversity of tRNA (the tRNA structure was taken from RCSB protein data bank (PDB), file 3IOu)
Fig. 2
Fig. 2
Functions of tRNA modifications
Fig. 3
Fig. 3
The Watson–Crick and wobble base pairs of uridine and 2-thiouridine with adenosine and guanosine
Fig. 4
Fig. 4
Mitochondrial tRNA nucleoside modifications. a Distribution of post-transcriptional modifications in mt-tRNA [90, 95]; modifications identified in mammalian mt-tRNAs are indicated in red [94]; b chemical structures of mitochondria-specific modifications located at the anticodon wobble position: 5-formylcytidine (f5C), 5-taurinomethyluridine (τm5U), and 5-taurinomethyl-2-thiouridine (τm5s2U); and in position 37: N6-isopentenyladenosine (i6A), 2-methylthio-N6-isopentenyladenosine (ms2i6A), N6-threonylcarbamoyladenosine (t6A), and 1-methylguanosine (m1G)
Fig. 5
Fig. 5
Base pairing between modified uridines and guanosine. a The conventional wobble base pair between mnm5U or mnm5S2U and guanosine; b base pairing of a H2U-type nucleoside with guanosine (X = H for H2U, X = S for a model proposed for a novel base pair between zwitter ionic mnm5S2U and guanosine, X = geS for mnm5geS2U)
Fig. 6
Fig. 6
mRNA modifications and their functions. 5′- and 3′-untranslated regions (UTR), as well as start (AUG) and stop (UGA) codons are indicated. The colors of the marks along the mRNA correspond to the specific modified nucleosides

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