Impact of Chemical Modification on tRNA Function

Abstract

Post‐transcriptional tRNA modifications play a critical role in ensuring a high‐quality pool of tRNA for participation in cellular translation. Despite their importance, important questions remain about the impacts of individual tRNA modifications on tRNA structure and function. Similarly, biological consequences of the absence of tRNA modifications have begun to be characterised in detail only recently. tRNA modifications have important impacts on biology, ranging from important impacts on individual tRNA molecules, to powerful effects on cellular function, and finally important roles in human health and disease.

Key Concepts

  • tRNA modifications occur at high frequency and with great chemical diversity.
  • tRNA modifications fine‐tune tRNA structure and function.
  • Through their effects on individual tRNA molecules, the impacts of tRNA modifications propagate to the cellular and organismal levels.
  • tRNA modifications can regulate translation and impact protein homeostasis.
  • Lack of tRNA modifications has been implicated in human diseases, such as neurological disorders, glucose metabolic defects and cancer.

Keywords: tRNA biology; tRNA modifications; translational regulation; RNA quality control

Figure 1. Roles for tRNA modifications in biology. Impacts of modifications have been described at various levels, ranging from impacts on individual tRNA structure and function (top), on cellular pathways (middle) and on multicellular organisms, as evident from effects on human health and disease (bottom). For each category, the impacts listed are those that are discussed in this article.
Figure 2. Biologically important tRNA modifications are found throughout the tRNA molecule. Secondary structure diagrams of a representative tRNA structure indicate specific locations of modifications that affect each of the three levels of biological function, as described in this article. Nucleotide positions specifically referred to in the text are indicated by numbers next to each coloured position, with the anticodon nucleotide numbering highlighted in red. Colour of the circles for each nucleotide position indicates the kingdom associated with each modification, with Bacteria (blue), Eukarya (red), or both (purple), as indicated.
Figure 3. Impact of tRNA modifications in the anticodon region is complex and context‐dependent. (a) mnm5s2U34 modification (blue) in E. coli helps tRNALys discriminate between cognate Lys (left) and noncognate Asn (right) codons by promoting base pairing with purine nucleotides at the 3rd codon position, and disfavoring base pairing with pyrimidine nucleotides at this position (note 5′‐3′ directionality of mRNA shown on diagram). (b) mcm5s2U34 (blue) and t6A37 (purple) modifications in S. cerevisiae stabilise codon–anticodon mismatches for certain nucleotide combinations at the second position of tRNAGlu (left) and second and third positions of tRNALys (centre), respectively, but t6A37 (purple) destabilises certain mismatches at the first position of tRNALys (right).
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Further Reading

Bednářová A, Hanna M, Durham I, et al. (2017) Lost in translation: defects in transfer RNA modifications and neurological disorders. Frontiers in Molecular Neuroscience 10: 135.

Cosentino C, Cnop M and Igoillo‐Esteve M (2019) The tRNA epitranscriptome and diabetes: emergence of tRNA hypomodifications as a cause of pancreatic beta‐cell failure. Endocrinology 160: 1262–1274.

Hopper AK and Huang H‐Y (2015) Quality control pathways for nucleus‐encoded eukaryotic tRNA biosynthesis and subcellular trafficking. Molecular and Cellular Biology 35: 2052–2058.

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Schimmel P (2017) The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis. Nature Reviews Molecular Cell Biology 19: 45.

Torres AG, Batlle E and Ribas de Pouplana L (2014) Role of tRNA modifications in human diseases. Trends in Molecular Medicine 20: 306–314.

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Howell, Nathan W, and Jackman, Jane E(Nov 2019) Impact of Chemical Modification on tRNA Function. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028527]