Fig. 2
From: tRNA-derived small RNAs in human cancers: roles, mechanisms, and clinical application
Biogenesis and classification of tsRNAs. Pre-tRNAs are first transcribed from tRNA genes via RNA polymerase III in the nucleus, which undergo a series of processing and modification processes (e.g., m5C, m7G, and Ψ) and are converted into active mature tRNAs. tsRNAs can be broadly categorized into tiRNAs and tRFs as per the cleavage sites within tRNAs. Under stress conditions, tiRNAs are produced through ANG cleavage of the anticodon loops found in mature tRNAs, encompassing 5’-tiRNAs and 3’-tiRNAs. tRFs emerge from pre-tRNAs or fully mature tRNAs and are categorized per the initial cleavage sites into tRF-1, tRF-3, tRF-5, tRF-2, and i-tRF. Specifically, tRF-1 arises from the cleavage of pre-tRNA facilitated by endonuclease (RNase Z/ELAC2). tRF-3 can arise from the cleavage of the TΨC loop within mature tRNAs, a process facilitated by enzymes such as Dicer and ANG. This category is then subdivided into tRF-3a and tRF-3b. Additionally, tRF-5 is produced via cleavage of the D-loop, D stem, or 5’ half of the anticodon stem of mature tRNAs by Dicer and is classified as tRF-5a, tRF-5b, and tRF-5c. tRF-2 is produced by anticodon loops under hypoxic stress stimulation. i-tRF is mainly generated from the internal regions of mature tRNAs and is classified as A-tRF, D-tRF, and V-tRF.