Small Non-coding Transfer RNA-Derived RNA Fragments (tRFs): Their Biogenesis, Function and Implication in Human Diseases

Fu, Yu; Lee, Inhan; Lee, Yong Sun; Bao, Xiaoyong

A mature tRNA has a 5ËŠ-monophosphate group and 3ËŠ-CCA charged with cognate amino acid. All properly folded tRNAs, with so called a cloverleaf structure, have four base-paired stems (in 5ËŠ-3ËŠ direction: D arm, anticodon arm, T arm, and acceptor stem) bridging the conserved D-loop, tRNA-specific anticodon loop, variable loop, and T-loop. Primary transcripts (pre-tRNAs) undergo several stages of maturation before becoming translation-competent tRNAs [26] . Compared to a mature tRNA, a pre-tRNA lacks a CCA tail but includes a 5ËŠ-leader starting with triphosphate, a 3ËŠ-trailer with an oligouridine stretch and, for intron-containing tRNA, a variably-sized intron. The 5ËŠ-and 3ËŠ-end of a pre-tRNA are trimmed by the endonucleases RNase P and RNase Z respectively, and an intron is spliced if there is [27, 28] . The 'CCA' acceptor stem must be added to the 3ËŠend as this is not encoded in eukaryotes [29] . While mature, uncleaved tRNAs have a well-defined role in protein translation, multiple groups have cloned and sequenced shorter tRNA fragments [30] . These fragments (termed "tRFs") identified so far can be classified into three groups; tRF-5 series whose 5ËŠ-end is aligned to the 5ËŠ-end of mature tRNA, tRF-3 series whose 3ËŠ-end is aligned to the 3ËŠ-end of mature tRNA, and tRF-1 series which is the 3ËŠ-trailer sequence in a pre-tRNA and released during 3ËŠ-end processing (Fig. 1) . Some groups have also termed the tRF-5 or tRF-3 series as tRF halves or type I [31, 32] and tRF1 series as type II [32] .