tRNA-Derived Small RNAs: Biogenesis, Modification, Function and Potential Impact on Human Disease Development

Abstract

Transfer RNAs (tRNAs) are abundant small non-coding RNAs that are crucially important for decoding genetic information. Besides fulfilling canonical roles as adaptor molecules during protein synthesis, tRNAs are also the source of a heterogeneous class of small RNAs, tRNA-derived small RNAs (tsRNAs). Occurrence and the relatively high abundance of tsRNAs has been noted in many high-throughput sequencing data sets, leading to largely correlative assumptions about their potential as biologically active entities. tRNAs are also the most modified RNAs in any cell type. Mutations in tRNA biogenesis factors including tRNA modification enzymes correlate with a variety of human disease syndromes. However, whether it is the lack of tRNAs or the activity of functionally relevant tsRNAs that are causative for human disease development remains to be elucidated. Here, we review the current knowledge in regard to tsRNAs biogenesis, including the impact of RNA modifications on tRNA stability and discuss the existing experimental evidence in support for the seemingly large functional spectrum being proposed for tsRNAs. We also argue that improved methodology allowing exact quantification and specific manipulation of tsRNAs will be necessary before developing these small RNAs into diagnostic biomarkers and when aiming to harness them for therapeutic purposes.

To be or not to be modified: Miscellaneous aspects influencing nucleotide modifications in tRNAs

“…In addition, an increase of wobble cmo 5 U34 in tRNA Thr(UGU) of Mycobacterium bovis in response to hypoxia was reported to promote translation of specific transcripts enriched in the ACG codon, including the DosR master regulator of hypoxia, here again linking stress‐induced tRNA modification changes to translation reprogramming . Finally, it is worth to briefly mention that tRNA modifications have been linked to stress response via a seemingly unrelated mechanism implicating tRNA stress‐induced cleavage and the formation of tRNA‐derived small‐RNAs, with some tRNAs becoming more sensitive to endonucleolytic cleavage in the absence of m 5 C modifications .…”

“…This suggests that modifications do not have the same beneficial effect for all tRNAs, and that the introduction of certain modifications in some tRNAs is the consequence of the presence of modification enzymes important for other tRNA species (19). In addition to these functions in decoding and stability, modifications in tRNAs are also affecting alternative functions of tRNAs outside translation, making all aspects of tRNA biology controlled and modulated by modifications (1,4,9). Collectively, the introduction of modifications at appropriate positions in tRNAs is of primary importance for optimal cell function.…”

Time-resolved NMR monitoring of tRNA maturation

“…All cellular functions of tRNAs, including their alternative functions outside translation, are controlled and modulated by modifications (5,9,10). While modified nucleotides in the ACL participate in decoding during protein synthesis (11,12), those in the tRNA core are collectively implicated in the folding and stability of tRNAs (13).…”

The tRNA‐associated dysregulation in immune responses and immune diseases

“…Typically, tRNAs in the cytoplasm have a length of 73-90 nucleotides, while mitochondrial tRNAs (mt-tRNAs) have only 57. 11 The mature tRNAs are characterized by a "clover" secondary structure with a D-loop, an anticodon loop, a variable loop, a T-loop and an acceptor arm, as well as an L-shaped tertiary structure maintained by hydrogen bonds. 12 Generally, aminoacyl-tRNAs recognize 61 triplet codons in mRNAs and decode them into 20 standard amino acids in the translation machinery.…”