Emerging functional principles of tRNA-derived small RNAs and other regulatory small RNAs.

Recent advancements in small RNA sequencing have unveiled a previously hidden world of regulatory small non-coding RNAs (sncRNAs) that extend beyond the well-studied siRNAs, miRNAs, and piRNAs. This exploration, starting with tRNA-derived small RNAs (tsRNAs), has led to the discovery of a diverse universe of sncRNAs derived from various structured RNAs such as rRNAs, snoRNAs, snRNAs, Y RNAs, and Vault RNAs, with exciting uncharted functional possibilities. In this perspective, we discuss the emerging functional principles of sncRNAs beyond the well-known RNAi-like mechanisms, focusing on those that operate independent of linear sequence complementarity but rather function in an aptamer-like fashion. Aptamers use 3D structure for specific interactions with ligands and are modulated by RNA modifications and subcellular environments. Given that aptamer-like sncRNA functions are widespread and present in species lacking RNAi, they may represent an ancient functional principle that predates RNAi. We propose a rethinking of the origin of RNAi and its relationship with these aptamer-like functions in sncRNAs, and how these complementary mechanisms shape biological processes. Lastly, the aptamer-like function of sncRNAs highlights the need for caution in using small RNA mimics in research and therapeutics, as their specificity is not restricted solely to linear sequence.