Abstract
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.
Highlights
All ribonucleic acid (RNA) species carry modified nucleosides that have been implicated in various biological roles, such as RNA homeostasis, coding, decoding, regulation and expression of genes [1,2]
Many modifications within the structural core of the tRNA are essential for stabilizing the overall molecular structure; loss of these modifications can result in rapid degradation of hypomodified tRNAs [6]
The translation of NAU is mediated by base modifications of the anticodon tRNA loop, which adapt its geometry to the mRNA codon in the ribosome
Summary
All ribonucleic acid (RNA) species carry modified nucleosides that have been implicated in various biological roles, such as RNA homeostasis, coding, decoding, regulation and expression of genes [1,2]. The greatest diversity of hypermodified nucleotides occurs at positions 34 and 37 of the anticodon of tRNAs (figure 1) Modifications at these positions ensure base pairing flexibility during decoding and reading frame maintenance [3,16], and have been shown to expand the ability of tRNAs to read additional codons [8]. It is important to investigate how nucleoside modifications influence the translational efficiency at the codon level In this context, ribosome profiling is an emerging technique that uses next-generation sequencing to monitor in vivo translation and allows identification of the amount of specific proteins that are produced by cells [33]. If a ribosome stalls at a specific codon, an increase of the respective footprint will be observed, and this information can be used to determine codon-specific translation elongation rates Together, these technological advances provide novel insights into how tRNA modifications affect mRNA decoding. In the final section of this review, we develop a mechanistic framework for how these modifications can be used for translational genome recoding
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