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Review
, 5 (1)

Metazoan tsRNAs: Biogenesis, Evolution and Regulatory Functions

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Review

Metazoan tsRNAs: Biogenesis, Evolution and Regulatory Functions

Shengqian Dou et al. Noncoding RNA.

Abstract

Transfer RNA-derived small RNAs (tsRNAs) are an emerging class of regulatory non-coding RNAs that play important roles in post-transcriptional regulation across a variety of biological processes. Here, we review the recent advances in tsRNA biogenesis and regulatory functions from the perspectives of functional and evolutionary genomics, with a focus on the tsRNA biology of Drosophila. We first summarize our current understanding of the biogenesis mechanisms of different categories of tsRNAs that are generated under physiological or stressed conditions. Next, we review the conservation patterns of tsRNAs in all domains of life, with an emphasis on the conservation of tsRNAs between two Drosophila species. Then, we elaborate the currently known regulatory functions of tsRNAs in mRNA translation that are independent of, or dependent on, Argonaute (AGO) proteins. We also highlight some issues related to the fundamental biology of tsRNAs that deserve further study.

Keywords: Argonaute; stress response; tRNA-derived small RNAs; translational regulation; tsRNAs.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The biogenesis of tRNA-derived small RNAs (tsRNAs) from mature transfer RNAs (tRNAs). (A) Processing and classification of tsRNAs derived from mature tRNAs. The cleavage of an RNase at the D-loop or T-loop of a tRNA can generate a 5′ or 3′ tsRNA, respectively. The 5′ tsRNA could be generated by DCR, while 3′ tsRNA could be produced by DCR or ANG. Other unknown RNases (?) might also participate in tsRNA generation. The tRNA halves are cleaved by Rny1 and angiogenin (ANG) in yeasts and mammals, respectively. (B) The conservation patterns of Rny1 and ANG in eukaryotes. Among the five representative species, ANG is only present in humans and mice. Although the homologous sequence of Rny1 can be found in all the five species, currently Rny1 is only demonstrated to be involved in the biogenesis of tRNA halves in yeasts.
Figure 2
Figure 2
The Argonaute (AGO)-independent translation regulation modes mediated by tsRNAs. (A) In human cells, the multi-synthetase complex (MSC) can associate with elongation factors (EFs) to deliver charged tRNAs to the ribosomes. A 5′-tsRNAGln interferes with this process by interacting with MSC, which impedes protein translation. (B) In Haloferax volcanii, 5′-tsRNAVal can bind to small ribosomal subunits, which inhibits formation of the translation initiation complex and reduces protein translation under stress conditions. (C) Certain oncogenic mRNAs are stabilized if their 3′ UTRs are bound by YBX1. In breast cancer cells, several tsRNAs can competitively bind to YBX1, which destabilizes such oncogenic mRNAs by displacing them from YBX1. (D) A 22-nt 3′tsRNA-LeuCAG binds the mRNAs of two ribosomal proteins (RPS28 and RPS15) to unfold their secondary structures and enhance their translation. For RPS28 mRNA, one target site of 3′tsRNA-LeuCAG is located in the coding sequence (CDS) and the other target site is located in 3′UTR; for RPS15 mRNA, the tsRNA target site is located in CDS.
Figure 3
Figure 3
AGO-dependent tsRNA-mediated regulation. (A) tsRNAs are bound by AGO proteins in various species. In humans, tsRNAs are preferentially associated with AGO3 and 4 over AGO1 and 2 [68], and tsRNAs are also bound by Hiwi2 [65]. In Drosophila, tsRNAs are bound by AGO1, AGO2, AGO3, PIWI, and AUB. In S2 cells, tsRNAs are preferentially bound by AGO2 over AGO1 [23]. tsRNAs are also bound by Miwi2 in mice [65], by MARWI in the common marmoset [66], by BmAgo2 in silkworms [64], by Twi12 in ciliates [61,62], and by AGO1, 2, 4 and 7 in plants [63]. (B) The tsRNA-mRNA chimeras that are bound by AGO1 as revealed by human cross-linking, ligation and sequencing of hybrids (CLASH) data. (C) Drosophila tsRNAs suppress global translation by impeding ribosome biogenesis. Drosophila AGO2-bound tsRNAs preferentially inhibit translation of mRNAs of the ribosome proteins (RPs) or translational initiation or elongation factors (IEFs) through a RNAi-like approach, leading to attenuated global translation. Meanwhile, the processing of tRNA into tsRNAs also inhibits global translation since the abundance of tRNAs is reduced.

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