Lost in Translation: Defects in Transfer RNA Modifications and Neurological Disorders

Abstract

Transfer RNAs (tRNAs) are key molecules participating in protein synthesis. To augment their functionality they undergo extensive post-transcriptional modifications and, as such, are subject to regulation at multiple levels including transcription, transcript processing, localization and ribonucleoside base modification. Post-transcriptional enzyme-catalyzed modification of tRNA occurs at a number of base and sugar positions and influences specific anticodon-codon interactions and regulates translation, its efficiency and fidelity. This phenomenon of nucleoside modification is most remarkable and results in a rich structural diversity of tRNA of which over 100 modified nucleosides have been characterized. Most often these hypermodified nucleosides are found in the wobble position of tRNAs, where they play a direct role in codon recognition as well as in maintaining translational efficiency and fidelity, etc. Several recent studies have pointed to a link between defects in tRNA modifications and human diseases including neurological disorders. Therefore, defects in tRNA modifications in humans need intensive characterization at the enzymatic and mechanistic level in order to pave the way to understand how lack of such modifications are associated with neurological disorders with the ultimate goal of gaining insights into therapeutic interventions.

Keywords: Q-tRNA; modified nucleosides; neurological disease; queuosine; transfer RNA modifications.

Figure 1

(A) Schematic representation of the secondary structure of transfer RNA (tRNA) with post-transcriptionally modified residues in light orange and red (numbered). The residues marked in red are of relevance to human neurological disorders. The abbreviations for the modifications are as follows: m²₂G: N2, N2-dimethyl guanosine; m⁵C: 5-methylcytosine; I34: inosine at position 34; Q34: queuosine at position 34, mcm⁵U: 5-methoxycarbonylmethyluridine; mcm⁵s²U: 5-methoxycarbonylmethyl-2-thiouridine; ψ: pseudouridine; t⁶A37: N⁶-threonyl-carbamoyl-adenosine at position 37. (B) Queuosine modification of tRNA. The G₃₄U₃₅N₃₆ anticodon sequence of tRNA isoacceptors for amino acids tyrosine, asparagine, aspartic acid and histidine will base pair with a N₁A₂C/U₃ codon of mRNA. G = guanine, U = uridine, A = adenine, N = any base. (C) Single step of Q modification of tRNAs in eukaryotes showing replacement of G₃₄ by Q in the anticodon triplet by the enzyme heterodimeric TGT enzyme complex. Free Queuosine, Queuosine-5′-P, Queuosine-3′-P are obtained from degradation of Q-tRNA. Salvage of Q is accomplished by protein DUF2419.