Origins and evolving functionalities of tRNA-derived small RNAs

tRNA-derived small RNAs (tsRNAs) are present across all three domains of life: Archaea, Bacteria, and Eukarya. The biogenesis of tsRNAs involves specific cleavage of mature tRNAs or tRNA precursors at preferred loci followed by further processing. RNA modifications are essential for both tsRNA biogenesis and functionality. tsRNA functionality is intricately linked to basic life elements including the ribosomal machinery and viral replication, in addition to binding to ribonucleoprotein and Argonaute proteins (i.e., AGO and PIWI). tsRNAs can move across tissues/cells and may mediate intergenerational phenotype transmission and pathogen–host interplay and symbiosis. tsRNAs and their RNA modifications can serve as disease biomarkers. 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 fundamental 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 modifications, 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. 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 fundamental 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 modifications, 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. also termed tRNA ligases, aaRSs are enzymes that catalyze the acylation of a specific amino acid or its precursor to one of its cognate tRNAs to form an aminoacyl-tRNA. a large quaternary protein structure formed in the process of apoptosis, the formation of which is triggered by the release of cytochrome c from the mitochondria. a post-translational modification mediated by arginyl-tRNA–protein transferase (ATE1) that transfers arginine from tRNA onto proteins. evolutionarily conserved proteins in both prokaryotes and eukaryotes that play an essential role in gene silencing. These can be subdivided into the AGO subfamily and the PIWI subfamily according to their phylogenetic classification. algorithms that aim to recognize underlying relationships in a dataset through a process that mimics the way the human brain operates. a small hemoprotein that is loosely associated with the inner membrane of the mitochondrion, and which triggers cell apoptosis on being released into the cytosol in response to apoptotic stimuli. a part of the broader family of machine learning methods. the smallest virus that is known to infect animals; HDV has a single-stranded circular RNA genome. the most recent common ancestor (most likely a single-celled organism) of all current life on Earth. a self-organized, endogenously ordered, spherical collection of lipids that has been proposed as a stepping-stone toward the origin of life. ribosomes of distinct compositions within a cell or across tissues that generate biased translational specificity for different mRNA subpopulations. extracellular RNases that can enter host cells and cleave essential RNAs such as rRNAs and tRNAs. RNA molecules that catalyze specific biochemical reactions similarly to the action of protein enzymes. ribonucleoprotein (RNP) granules in the cytoplasm which aggregate stalled translational preinitiation complexes and nontranslating mRNAs that accumulate during stress. a conserved structure arising from the interaction between the D- and T-loops of a tRNA. the smallest known infectious pathogens which are composed solely of a circular, single-stranded RNA that has no protein coating.