tRNA fragments in human health and disease

Abstract

Transfer RNA (tRNA) is traditionally considered to be an adaptor molecule that helps ribosomes to decode messenger RNA (mRNA) and synthesize protein. Recent studies have demonstrated that tRNAs also serve as a major source of small non-coding RNAs that possess distinct and varied functions. These tRNA fragments are heterogeneous in size, nucleotide composition, biogenesis and function. Here we describe multiple roles that tRNA fragments play in cell physiology and discuss their relevance to human health and disease.

Keywords: Angiogenin; Apoptosis; RNA processing; Stress; Transfer RNA; tRNA-derived fragment.

Fig. 1

Processing of precursor and mature forms of tRNA in tRNA fragments. (A) Processing of precursor tRNA. Transcribed pre-tRNA contains distinct 5′- and 3′-extensions (5′-leader and 3′-trailer (blue)) that have to be removed by RNase P and RNase Z during tRNA processing. In some cases, the 5′-leader is not removed giving rise to 5′-leader exon fragments. Intron (blue)-containing pre-tRNAs are spliced by the TSEN complex. Usually, such introns are quickly degraded but in some pathological cases linear introns can accumulate. 5′-exons and 3′-exons are naturally present in the nucleus as products of intron-containing tRNA splicing. Upon 3′-trailer removal, the CCA-adding enzyme TRNT1 adds CCA to the 3′-ends of tRNA. In some cases, 3′-trailers accumulate and are exported to the cytoplasm as 3′-U tRFs. (B) Processing of mature cytoplasmic tRNA. Mature tRNA can be cleaved in the anticodon loop by angiogenin (ANG) to produce 5′- and 3′-tRNA halves (or 5′- and 3′-tiRNAs, respectively. Dicer-dependent cleavage of tRNA in the D arm of tRNA results in the production of small tRNA fragments, 5′-tRFs. Similarly, cleavage in the T arm by Dicer or ANG results in the production of tRFs containing CCA at their 3′-ends (so called 3′CCA tRFs). Both 5′-tRFs and 3′CCA tRFs may also be processed from 5′- and 3′-tRNA halves, respectively (dashed arrows).