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tRNA introns: Presence, processing, and purpose

Advanced Review

Casey A. Schmidt, A. Gregory Matera

Published Online: Dec 28 2019

DOI: 10.1002/wrna.1583

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Abstract The presence of introns in both protein‐coding and noncoding RNA transcripts is a fascinating phenomenon. It seems counterintuitive that an organism would devote precious time and energy to removing a nucleic acid sequence that will not be present in the final product. Nevertheless, introns (including self‐splicing ones) are clearly important components of the basic cellular process of gene expression. Transfer RNA (tRNA) introns have been detected in all three kingdoms of life, and their precise removal is crucial for tRNA function. Of particular interest to this review are the tRNA intronic circular RNAs (tricRNAs) that form during metazoan tRNA splicing. In animal cells, these ultrastable introns form a novel class of noncoding RNA. Here, we summarize established knowledge and describe new findings in the field of tRNA splicing. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA in Disease and Development > RNA in Disease RNA Processing > tRNA Processing

Comparison of the intron–exon boundaries in (a) archaea and (b) eukaryotes. Exonic bases are shaded black and intronic bases are gray; the white bases correspond to the anticodon. The endonuclease cut sites are denoted by red lines. The proximal base pair is highlighted in green. Blue lines represent base pairs

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Distribution of isodecoders among various organisms. Data obtained from the genomic tRNA database (Chan & Lowe, ); human data are in agreement with an experimental verification of tRNA gene expression (Gogakos et al., ). D. mel, Drosophila melanogaster. C. ele, C. elegans. M. mus, Mus musculus. H. sap, Homo sapiens. H. vol, Haloferax volcanii

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Distribution of intron‐containing tRNA genes in various organisms. Data obtained from the genomic tRNA database (Chan & Lowe, , ). P. aer, Pyrobaculum aerophilum. H. vol, Haloferax volcanii. S. pom, Schizosaccharomyces pombe. S. cer, Saccharomyces cerevisiae. D. mel, Drosophila melanogaster. C. ele, C. elegans. X. tro, Xenopus tropicalis. D. rer, Danio rerio. M. mus, Mus musculus. H. sap, Homo sapiens

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Model of Clp1 as a negative regulator of tRNA and tricRNA biogenesis. Upon cleavage of the pre‐tRNA by TSEN, the 5′‐OH found on both the intron and 3′ tRNA exon could be phosphorylated by Clp1, perhaps in response to a cellular signal or stress. Phosphorylated 5′ ends cannot be ligated by RtcB‐type ligases, making Clp1 a negative regulator of tRNA splicing. The products of the Clp1 reaction might be degraded or could conceivably participate in downstream signaling events, wherein Clp1 phosphorylation could be a previously uncharacterized mechanism to generate tRNA halves

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Potential uses of tricRNAs in a research capacity. (a) tricRNAs could be engineered with specific sequences to act as miRNA (left) or RBP (right) sponges. (b) An IRES‐ and ORF‐containing tricRNA could act as a stable template for protein translation in order to generate a therapeutic protein. (c) tricRNAs expressed from a transgenic construct could serve as an orthogonal method to generate circRNAs in the study of circRNA biogenesis and function

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Diagram of the “Direct ligation” and “Healing and sealing” tRNA splicing pathways. For simplicity, the direct ligation enzymes and the cleavage complex depicted are from human; the healing and sealing enzymes depicted are from yeast. Pre‐tRNAs are cleaved by TSEN complex orthologs in organisms other than humans. In yeast and plants, Rlg1/Trl1 “heals” the broken RNA ends via its kinase and cyclic phosphodiesterase activities. The tRNA exons are then joined by the ligase domain activity (upper branch/orange arrows). Rlg1/Trl1 also phosphorylates the 5′ end of the intron, making it a substrate for the 5′ to 3′ exonuclease Xrn1. In archaea and metazoans, a single enzyme HSPC117/RtcB directly ligates the exon halves and intron ends (lower branch/blue arrows)

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