Noncanonical Roles of tRNAs: tRNA Fragments and Beyond

Abstract

As one of the most abundant and conserved RNA species, transfer RNAs (tRNAs) are well known for their role in reading the codons on messenger RNAs and translating them into proteins. In this review, we discuss the noncanonical functions of tRNAs. These include tRNAs as precursors to novel small RNA molecules derived from tRNAs, also called tRNA-derived fragments, that are abundant across species and have diverse functions in different biological processes, including regulating protein translation, Argonaute-dependent gene silencing, and more. Furthermore, the role of tRNAs in biosynthesis and other regulatory pathways, including nutrient sensing, splicing, transcription, retroelement regulation, immune response, and apoptosis, is reviewed. Genome organization and sequence variation of tRNA genes are also discussed in light of their noncanonical functions. Lastly, we discuss the recent applications of tRNAs in genome editing and microbiome sequencing. Expected final online publication date for the Annual Review of Genetics, Volume 54 is November 23, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Transfer RNA-Derived Fragments, the Underappreciated Regulatory Small RNAs in Microbial Pathogenesis

“…Besides their well-known function as amino acid carriers to decode mRNA sequences in eukaryotes, numerous non-canonical roles of tRNAs have been identified, including tRNA fragment mediated gene silencing through an Argonaute-microRNA like mechanism (Maute et al, 2013) and both negative and positive effects on global regulation of protein translation (Yamasaki et al, 2009;Kim et al, 2017). The roles of tRNA fragments in eukaryotes have been extensively reviewed (Keam and Hutvagner, 2015;Su et al, 2020). tRNA fragments were first described in Escherichia coli in response to bacteriophage infection (Levitz et al, 1990).…”

“…Advancements in sRNA sequencing technologies and bioinformatics tools have led to the discovery of transfer RNA (tRNA)-derived fragments, leading to functional studies that have elucidated the regulatory roles of these fragments (Su et al, 2020). In eukaryotes and prokaryotes, tRNAs are the most abundant RNA species by the number of molecules (Neidhardt, 1996;Palazzo and Lee, 2015) and are evolutionarily conserved.…”

On the Track of the Missing tRNA Genes: A Source of Non-Canonical Functions?

“…Interestingly, given the large size of the cellular tRNA population (which in higher eukaryotes is estimated to be around tens of millions of copies), it is expected that they participate in a large number of interactions with other macromolecules with a high degree of specificity in the context of several cellular processes besides protein synthesis ( Pan, 2018 ). Half a century has passed since the first reports on extra-ribosomal roles of tRNAs ( Soffer et al, 1969 ; Leibowitz and Soffer, 1970 ), and many evidence has accumulated on the so-called “non-canonical” functions of tRNAs to differentiate them from their key role in ribosomal protein biosynthesis ( Raina and Ibba, 2014 ; Katz et al, 2016 ; Schimmel, 2018 ; Su et al, 2020 ). The list continues to grow, most particularly with the increasing description of cellular properties of tRNA fragments that have received much attention during the last years.…”

“…Among tRNA roles outside ribosomal protein synthesis, the following have been previously highlighted: nutrient sensing, transcription regulation, retroelement insertion, translation kinetics and protein folding, stress response, immune response, apoptosis inhibition, peptidic antibiotic biosynthesis, bacterial wall biosynthesis, post-translational protein modification, membrane lipid modification, retroviral replication, mitochondrial ribosome assembly, and mitochondrial DNA replication ( Seligmann, 2010 ; Raina and Ibba, 2014 ; Katz et al, 2016 ; Balasubramaniam et al, 2017 ; Bogenhagen et al, 2018 ; Su et al, 2020 ; and this issue). Also, several roles have been described for tRNA fragments, among which the following stand out: gene silencing, translation regulation, transposable element regulation, noncoding RNA regulation, cell differentiation, cell proliferation and cancer, host defense, stress response, apoptosis, and epigenetic inheritance ( Magee and Rigoutsos, 2020 ; Polacek and Ivanov, 2020 ; Su et al, 2020 ; and this issue). In most cases, the information about the precise isotype, state of post-transcriptional modification, recognition by the cognate aminoacyl-tRNA synthetase, and aminoacylation state is still scarce, leaving the door open for new research avenues.…”

tRNAs as a Driving Force of Genome Evolution in Yeast

“…This interplay is fine-tuned by codon usage, which is under selective pressure and show variation across budding yeast species (LaBella et al, 2019). Yet tRNAs have other non-canonical roles in the biological theater beyond their role as adaptors in protein synthesis (reviewed in Raina andIbba, 2014 andSu et al, 2020). For example, tDNAs have roles in chromatin organization and gene regulation and are sites for binding of numerous chromatin proteins, including the architectural structural maintenance of chromosomes (SMC) proteins, nuclear pore proteins, chromatin remodelers, and histone modifiers (D'Ambrosio et al, 2008;Su et al, 2020).…”