tRNA Repertoire and Its Functional Significance

Overview

Transfer RNAs (tRNAs) are the physical link between mRNA codons and protein amino acid sequences (Fig. 1) and are the most abundant small non-coding RNA molecules. Despite this universality, genomes vary substantially in codon preference across coding sequences. The source of this bias is debated but likely reflects selection for translational efficiency and accuracy [1-3].

Many biological processes, including proliferation [4], differentiation [4, 5], and apoptosis [6], are accompanied by changes in tRNA levels. tRNA repertoire alterations affect cell-fate decisions during development (Fig. 2). Numerous diseases show disrupted tRNA levels and distributions, including type 2 diabetes [19], Huntington disease [16], and HIV infection [18]. Dysregulated tRNA repertoires can promote tumorigenesis and cancer progression [5, 8-15], making the tRNA repertoire a key focus of biological and disease research.

Fig. 1. tRNA: role, function, and biogenesis.

tRNA Repertoire and Its Functional Significance

Changes in tRNA levels can profoundly alter cell state. Codon usage differs between genes serving cell-autonomous functions and those involved in multicellularity. tRNAs induced by proliferation and differentiation often carry anticodons matching the codons enriched in these genes (Fig. 2), suggesting coordination between tRNA production and mRNA translation [4]. Overexpression of initiator tRNAi(Met) shifts the global tRNA expression profile and increases metabolic activity and proliferation [5]. tRNAs also regulate apoptotic sensitivity at cytochrome-c-mediated apoptosome formation [6], and microinjected tRNA inhibits cytochrome-c-induced apoptosis [7].

Fig. 2. tRNA pools are coordinated with mRNA transcriptome changes of different codon usage under differentiation or proliferation, affecting cell fate determination.

tRNA Repertoire and Disease

The tRNA repertoire has fundamental impact in human diseases. Many conditions are associated with disrupted tRNA levels, and dysregulation of certain tRNAs can induce tumorigenesis and cancer progression.

Cancer

Cataloguing the tRNA repertoire, Gingold et al. showed that tRNA pools differ between cancer and differentiated non-cancer cells [4]. tRNAs upregulated in differentiated or arrested cells are repressed in proliferating cells, and vice versa. Cancer cells adjust their tRNA pools to selectively bolster translation of mRNAs required for tumor progression. Comparing tumor and normal breast tissue, Pavon-Eternod et al. found distinct nuclear- and mitochondrial-encoded tRNA expression patterns, suggesting tRNAs as breast cancer biomarkers [8]. Goodarzi et al. confirmed that specific tRNAs are upregulated in human breast cancer cells as they gain metastatic activity [9]; tRNA-Glu-UUC and tRNA-Arg-CCG promote breast cancer metastasis by enhancing EXOSC2 and GRIPAP1 expression. These cases demonstrate that dysregulated tRNA repertoires promote tumorigenesis and cancer progression [5, 8-15].

Huntington's Disease

Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by expansion of a CAG-encoded polyglutamine (polyQ) repeat in huntingtin (Htt), with highly heterogeneous onset. Analyses of HD brain tissue reveal traces of polyalanine (polyA) or polyserine (polyS) proteins within polyQ aggregates, probably arising from frameshifts to Ala-encoding -1 GCA or Ser-encoding +1 AGC frames. Girstmair et al. showed that depletion of tRNA-Gln-CUG pairing to the CAG codon is the main cause of -1 frameshifting, and frameshifted proteins form morphologically distinct aggregates depending on the Q:A ratio. Frameshifting within expanded CAG stretches may thus contribute to the heterogeneous course and onset of HD [16].

Virus Infection

Viruses depend entirely on the host translation machinery. Viral codon usage is thought to adapt to the host tRNA pool; yet viral codon usage often appears poorly adapted. Profiling tRNA repertoires, Pavon-Eternod et al. found that influenza A and vaccinia viruses can manipulate tRNA populations to favor translation of their own genes [17]. HIV-1 is expressed extremely well in human cells despite poorly adapted codons: early gene codon usage resembles highly expressed human genes, while late gene codon usage adapts to the altered tRNA pool induced late in infection [18]. This is a striking example of a virus modulating the tRNA pool to optimize translation efficiency.

tRNA Roadmap

PCR arrays are reliable, accurate tools for analyzing the tRNA repertoire. Armed with tRNA repertoire data, gain-of-function [5, 20, 16] and loss-of-function [17] approaches support follow-up studies, and common non-coding RNA methods apply readily to in-depth tRNA research.

Fig. 3. tRNA research roadmap.

Reference

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