Origins and evolving functionalities of tRNA-derived small RNAs

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are among the most ancient small RNAs in all domains of life and are generated by the cleavage of tRNAs. Emerging studies have begun to reveal the versatile roles of tsRNAs in funda-mental biological processes, including gene silencing, ribosome biogenesis, retrotransposition, and epigenetic inheritance, which are rooted in tsRNA sequence conservation, RNA modifications, and protein-binding abilities. We summarize the mechanisms of tsRNA biogenesis and the impact of RNA modifi-cations, and propose how thinking of tsRNA functionality from an evolutionary perspective urges the expansion of tsRNA research into a wider spectrum, including cross-tissue/cross-species regulation and harnessing of the 'tsRNA code' for precision medicine.

Automated summary

tsRNA, derived from tRNA cleavage, are ancient small RNAs with versatile roles in fundamental biological processes. These roles stem from sequence conservation, RNA modifications, and protein-binding abilities, suggesting the need for expanding tsRNA research into broader areas for precision medicine.