The Biology of tRNA t6A Modification and Hypermodifications—Biogenesis and Disease Relevance Article Swipe
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· 2025
· Open Access
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· DOI: https://doi.org/10.1016/j.jmb.2025.169091
· OA: W4408957849
The structure and function of transfer RNAs (tRNAs) are highly dependent on post-transcriptional chemical modifications that attach distinct chemical groups to various nucleobase atoms at selected tRNA positions via enzymatic reactions. In all three domains of life, the greatest diversity of chemical modifications is concentrated at positions 34 and 37 of the tRNA anticodon loops. N<sup>6</sup>-threonylcarbamoyladenosine (t<sup>6</sup>A) is an essential and universal modification occurring at position 37 of tRNAs that decode codons beginning with an adenine. In a subset of tRNAs from specific organisms, t<sup>6</sup>A is converted into a variety of hypermodified forms, including cyclic N<sup>6</sup>-threonylcarbamoyladenosine (ct<sup>6</sup>A), hydroxy-N<sup>6</sup>-threonylcarbamoyladenosine (ht<sup>6</sup>A), N<sup>6</sup>-methyl-N<sup>6</sup>-threonylcarbamoyladenosine (m<sup>6</sup>t<sup>6</sup>A), 2-methylthio-N<sup>6</sup>-threonylcarbamoyladenosine (ms<sup>2</sup>t<sup>6</sup>A) and 2-methylthio-cyclic N<sup>6</sup>-threonylcarbamoyladenosine (ms<sup>2</sup>ct<sup>6</sup>A). The tRNAs carrying t<sup>6</sup>A or one of its hypermodified derivatives are dubbed as the t<sup>6</sup>A family. The t<sup>6</sup>A family modifications pre-organize the anticodon loop in a conformation that enhances binding to the cognate mRNA codons, thereby promoting translational fidelity. The dysfunctional installation of modifications in the tRNA t<sup>6</sup>A family leads to translation errors, compromises proteostasis and cell viability, interferes with the growth and development of higher eukaryotes and is implicated in several human diseases, such as neurological disorders, mitochondrial encephalomyopathies, type 2 diabetes and cancers. In addition, loss-of-function mutations in KEOPS complex-the tRNA t<sup>6</sup>A-modifying enzyme-are associated with shortened telomeres, defects in DNA damage response and transcriptional dysregulation in eukaryotes. The chemical structures, the molecular functions, the known cellular roles and the biosynthetic pathways of the t<sup>6</sup>A tRNA family are described by integrating and linking biochemical and structural data on these modifications to their biological functions.
