Overview
As a fundamental component in translation, transfer RNAs (tRNAs) serve as the physical link between the nucleotide sequence of mRNAs and the amino acid sequence of proteins (Fig.1). tRNAs are ubiquitous nucleic acid entities that are the most abundant of all small non-coding RNA molecules. Despite this universality, genomes exhibit substantial variations in their preference for specific codons across their coding sequences. The source of this bias, though still debated, likely reflects selection for translational efficiency and accuracy[1-3].
A wide variety of biological processes, such as cell proliferation[4], differentiation[4, 5] and apoptosis[6], are always accompanied with variation of tRNAs levels. Alterations of tRNA repertoire affect cell-fate choices during cell development (Fig. 2). Many diseases show disruptions to the levels and distributions of tRNAs, such as type 2 diabetes mellitus[19], Huntington disease[16], and HIV infection[18]. Dysregulated tRNA repertoire can promote tumorigenesis and cancer progression[5, 8-15]. tRNA repertoire has become an important aspect in the study of biological processes and human diseases.
Figure 1. tRNA: the role, function and biogenesis.
tRNA repertoire and its functional significance
Alterations of tRNA levels can profoundly change the cell state by various mechanisms. For example, codon usage is different between the genes serving cell-autonomous functions and the genes involved in multicellularity. tRNAs induced by proliferation and differentiation often carry anticodons that correspond to the codons enriched for these genes accordingly (Fig. 2), which suggests a coordination between tRNA production and mRNA translation[4]. Overexpression of initiator tRNAi(Met) significantly alters the global tRNA expression profile and increases the cell metabolic activity and cell proliferation[5]. At the level of cytochrome c-mediated apoptosome formation, tRNAs can regulate apoptotic sensitivity[6]. Microinjection of tRNA can inhibit cytochrome c-induced apoptosis[7].
Figure 2. tRNA pools are coordinated with the alterations in the mRNA transcriptomes with different codon usage under differentiation or proliferation conditions. The repertoire has the effects on the cell fate determination.
tRNA repertoire and disease
tRNA repertoire has fundamental impact in human diseases. Many diseases are associated with the disrupted tRNAs levels. Dysregulation of certain tRNAs can induce tumorigenesis and cancer progression.
Cancer
After cataloging the tRNA repertoire, Gingold et al demonstrated the tRNA pools are different between cancer and differentiated non-cancer cells[4]. tRNAs that are upregulated in differentiated/arrested cells are repressed in proliferating cells. Conversely, tRNAs whose levels are high in proliferating cells become low in differentiated/arrested cells. Cancer cells adjust their tRNA pools to selectively bolster translation of the mRNAs that are required for tumor progression. By comparing tRNA expression in tumor versus normal breast tissues, Pavon-Eternod et al found that nuclear- and mitochondrial-encoded tRNAs exhibit distinct expression patterns, indicating the potential of using tRNAs as biomarkers for breast cancers[8]. Recently, Goodarzi et al confirmed that specific tRNAs are upregulated in human breast cancer cells as they gain metastatic activity[9]. Further studies showed tRNAGlu-UUC and tRNAArg-CCG promote breast cancer metastasis by directly enhancing EXOSC2 and GRIPAP1 expression. These and other cases conclusively demonstrate dysregulated tRNA repertoire can promote tumorigenesis and cancer progression[5, 8-15].
Huntington’s disease
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a CAG-encoded polyglutamine (polyQ) repeat in huntingtin (Htt). The disease displays a highly heterogeneous etiopathology and disease onset. Analyses of HD-affected brain tissues revealed traces of polyalanine (polyA) or polyserine (polyS) proteins within the polyQ aggregates. These species probably result from a shift in the Gln-encoding CAG frame to an Ala-encoding -1 GCA frame or a Ser-encoding 1 AGC frame. But what is the role of translational frameshifting in the pathogenesis of polyQ diseases? Girstmair et al found that depletion of tRNAGln-CUG pairing to the CAG codon was the main cause of -1 frameshifting. In addition, frameshifted proteins form morphologically distinct aggregates in vivo dependent on the Q:A ratio. The results suggest that frameshifting within expanded CAG stretches may contribute to the heterogeneity in the course and onset of HD on both cellular and individual level[16].
Virus Infection
Viruses are wholly dependent on the host translation machinery to synthesize their proteins. Consequently, viral codon usage is thought to be under selective pressure to adapt to the host cell tRNA pool. Since host codon usage generally reflects the host tRNA pool, viral translation should be more efficient when viral codon usage is similar to that of the host genes. In many cases, however, viral codon usage seems poorly adapted to that of its host. After profiling the tRNA repertoire, 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 host cells despite their codons are poorly adapted to human host. In another research, it is found that the codon usage of HIV-1 early genes is similar to that of the highly expressed human genes, whereas the codon usage of the late genes is better adapted to the altered tRNA pool induced late in viral infection[18]. This is a striking example of the virus modulating the tRNA pool to optimize its translation efficiency.
tRNA Roadmap
PCR Arrays are the reliable and accurate tools for analyzing the tRNA repertorie. Armed with the tRNA repertoire data, gain-of-function[5, 20, 16] and lose-of-function[17] approaches are useful for follow up studies. Commonly used methods in non-coding RNA studies are readily applicable to in-depth tRNA research.
Figure 3. tRNA research roadmap
Related Products
nrStar™ tRNA PCR Array
nrStar™ tRF&tiRNA PCR Array
Reference
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