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


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

Vera Oberbauer et al. Genes (Basel).


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.

Keywords: RNA modifications; human disease; protein translation; small RNAs; tRNA; tRNA fragment.

Conflict of interest statement

The authors state no conflict of interest.


Figure 1
Figure 1
Transfer RNAs (tRNAs) give rise to various tRNA-derived small RNAs (tsRNAs). tRNAs are preferentially cleaved in open loop structures. Dicer enzymes, as well as unknown RNases cleave tRNAs in the D- or T-loops, producing short tsRNAs in a mostly stress-independent fashion (tsRNAsNonS,, see text). The activity of various anticodon ribonucleases (ACNases) targeting the anticodon loops produces longer tsRNAs, often during stress conditions (tsRNAsS, see text).
Figure 2
Figure 2
Specific tRNA modifications might influence tsRNA stability. Various tRNAs contain particular RNA modifications that inhibit the access of 3′-5′ exonucleases. In particular, the positioning of 2′-O-methylated nucleotides (Cm, Gm, Um) in open loop structures suggests that such modifications might stabilize produced tsRNAs against degradation.
Figure 3
Figure 3
The activity of tsRNAs has been implicated in various biological processes. A selection of reported and suggested functions for tsRNAsNonS (A) and tsRNAsS (B) in different model organisms.

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