tRFs

tRNA-derived fragments (tRFs) are a class of small non-coding RNAs generated from transfer RNA (tRNA) molecules. Found across bacteria, archaea, and eukaryotes, tRFs arise from precise endonucleolytic cleavages of mature tRNAs or their precursors rather than from random degradation. They are typically 14 to 40 nucleotides in length, with subtypes defined by their origin within the tRNA and by the processing pathway.

tRFs are categorized by their source within the tRNA or precursor. tRF-5s come from the 5' end of mature tRNAs; tRF-3s come from the 3' end of mature tRNAs; tRF-1s derive from the 3' trailer sequence of precursor tRNAs; internal tRFs (i-tRFs) originate from internal regions of the mature tRNA; and tiRNAs (tRNA halves) are produced by cleavage in the anticodon loop and are typically about 31–40 nt in length. In many organisms, tiRNAs are associated with cellular stress responses.

Biogenesis involves diverse nucleases. Angiogenin is known to generate tiRNAs under stress, while other enzymes such as Dicer and RNase Z/P contribute in various species or contexts. tRF production can be constitutive or stress-induced, and the resulting fragments can be found in the cytoplasm, nucleus, and extracellular vesicles.

Functional roles and significance of tRFs are diverse and actively studied. They can regulate gene expression and translation, and some tRFs associate with Argonaute proteins to guide sequence-specific interactions with target RNAs, in a manner reminiscent of microRNAs. Others influence ribosome function or stress signaling. Altered tRF levels have been linked to cancer, neurodegenerative diseases, and viral infections, and tRFs are being explored as potential biomarkers and therapeutic targets.