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.
Highlights
Reviewed by: Baojin Ding, University of Texas Southwestern Medical Center, USA Hong Qing, Beijing Institute of Technology, China
This phenomenon of nucleoside modification is most remarkable and results in a rich structural diversity of Transfer RNAs (tRNAs) 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
Studies on such modifications were restricted to the ones that were the most abundant such as: peudouridine (ψ), N1-methyladenosine (m1A) and 2 -O-methylation (2 OMe) in ribosomal RNA and transfer RNA, and 2 OMe, N6-methyladenosine (m6A) in messenger RNA and viral RNA (Desrosiers et al, 1974; Perry and Kelley, 1974; Dubin and Taylor, 1975)
Summary
A major limitation in the study of the biological significance and function of tRNA base modifications has been the lack of a phenotype associated with such modifications under defined settings. The only tRNA with m5C at the wobble position is tRNALeu(CAA) and this uniqueness has a role in the regulation of translation in response to oxidative stress in cells (Chan et al, 2012; Gu et al, 2014). This has given rise to the concept of tRNA modification tunable transcripts (MoTTs; Endres et al, 2015). This concept is defined as tRNA modifications that lead to: (a) transcripts that use specific degenerate codons and codon biases to encode critical stress response proteins; and (b) transcripts whose translation is influenced by changes in wobble base tRNA modification
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