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.
Highlights
Transfer RNAs represent the second most abundant RNA species in all cells playing a central role in the decoding of messenger RNA during protein translation
Injection of small RNAs into fertilized zygotes resulted in gene expression changes of metabolic pathways and islets of the offspring [147] and RNAi-mediated knockdown of particular tRNA-derived small RNAs (tsRNAs) resulted in the upregulation of specific genes that contained sequences derived from endogenous retro-elements (MERVL) [131]
The growing number of reports on the astounding diversity of tsRNA-mediated functional consequences indicate that tsRNAs represent versatile modulators of various cellular processes and serve as conduits of information transfer across generations
Summary
Transfer RNAs (tRNAs) represent the second most abundant RNA species in all cells playing a central role in the decoding of messenger RNA (mRNA) during protein translation Besides this canonical function, tRNAs are involved in numerous additional cellular pathways and metabolic processes. Other processes might be specific for only prokaryotic cells, such as the use of tRNAs as amino acid donors for cell wall biosynthesis (reviewed in Reference [5]), or have only been observed in eukaryotic cells, such as tRNAs affecting the modulation of apoptosis [6] or the use of tRNAs as primers during retroviral replication [7] Both eukaryotic and prokaryotic tRNAs can give rise to various small RNAs, which appear to be not just remnants of tRNA maturation processes, nor are they mere tRNA degradation products. Since tRNAs are such ancient ‘molecular tools’ it is rather likely that their (multi-)functionality has been extensively tested throughout evolution resulting in additional ‘usability modes’ beyond their primary role in protein biosynthesis
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