The Biology of tRNA tA Modification and Hypermodifications-Biogenesis and Disease Relevance.

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-threonylcarbamoyladenosine (tA) 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, tA is converted into a variety of hypermodified forms, including cyclic N-threonylcarbamoyladenosine (ctA), hydroxy-N-threonylcarbamoyladenosine (htA), N-methyl-N-threonylcarbamoyladenosine (mtA), 2-methylthio-N-threonylcarbamoyladenosine (mstA) and 2-methylthio-cyclic N-threonylcarbamoyladenosine (msctA). The tRNAs carrying tA or one of its hypermodified derivatives are dubbed as the tA family. The tA 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 tA 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 tA-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 tA tRNA family are described by integrating and linking biochemical and structural data on these modifications to their biological functions.