Genome recoding by tRNA modifications

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.

Queuosine‐modified tRNAs confer nutritional control of protein translation

“…Cytosine‐5 methylation (m 5 C) is a widely known modification in the context of DNA methylation and epigenetic gene regulation (Jones, ). Interestingly, m 5 C also represents a conserved RNA modification (Gilbert et al , ), and several recent studies have provided evidence for a conserved role in the regulation of protein translation (Tuorto & Lyko, ). We have previously shown that Dnmt2‐mediated tRNA methylation affects the speed and accuracy of protein translation (Tuorto et al , ).…”

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

“…3). Individual anticodon domain modified nucleosides are identity determinants for protein recognition, particularly aminoacylation, 15-17 increase accuracy and efficiency in codon recognition, 18-24 and pre-structure the ASL for translation. 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.…”

“…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.…”

Rewriting the Genetic Code

“…Second, anticodons corresponding to sense codons are often the most important recognition element for aaRSs (39, 64); therefore, the three recoded genome projects are carefully focusing on Ala, Ser, and Leu codons whose cognate aaRS enzymes do not recognize the anticodon as an identity element (71, 113, 149). In addition, base modification of tRNAs is also important for accurate translation and restricted/extended codon decoding by tRNA (40) in not only a static but also a dynamic manner (142). Modified or unmodified U34 in an anticodon could be paired with any nucleotide at the wobble position of codons in the ribosome.…”