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Controlling translation via modulation of tRNA levels

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Transfer RNAs (tRNAs) are critical adaptor molecules that carry amino acids to a messenger RNA (mRNA) template during protein synthesis. Although tRNAs have commonly been viewed as abundant ‘house‐keeping’ RNAs, it is becoming increasingly clear that tRNA expression is tightly regulated. Depending on a cell's proliferative status, the pool of active tRNAs is rapidly changed, enabling distinct translational programs to be expressed in differentiated versus proliferating cells. Here, I highlight several post‐transcriptional regulatory mechanisms that allow the expression or functions of tRNAs to be altered. Modulating the modification status or structural stability of individual tRNAs can cause those specific tRNA transcripts to selectively accumulate or be degraded. Decay generally occurs via the rapid tRNA decay pathway or by the nuclear RNA surveillance machinery. In addition, the CCA‐adding enzyme plays a critical role in determining the fate of a tRNA. The post‐transcriptional addition of CCA to the 3′ ends of stable tRNAs generates the amino acid attachment site, whereas addition of CCACCA to unstable tRNAs prevents aminoacylation and marks the tRNA for degradation. In response to various stresses, tRNAs can accumulate in the nucleus or be further cleaved into small RNAs, some of which inhibit translation. By implementing these various post‐transcriptional control mechanisms, cells are able to fine‐tune tRNA levels to regulate subsets of mRNAs as well as overall translation rates. WIREs RNA 2015, 6:453–470. doi: 10.1002/wrna.1287 This article is categorized under: Translation > Translation Regulation RNA Processing > tRNA Processing RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
Conserved structure of transfer RNAs (tRNAs). Mature tRNAs fold into a cloverleaf secondary structure (a) that is further folded into an L‐shaped tertiary structure (b). Aminoacyl‐tRNA synthetases catalyze the covalent attachment of the cognate amino acid (denoted AA) to the tRNA 3′ end, and the genetic code is read by base pairing between the tRNA anticodon and the mRNA codon. The acceptor stem is typically 7 base pairs long, the D stem 3–4 base pairs, the anticodon stem 5 base pairs, and the TψC stem 5 base pairs. As the name suggests, different tRNAs have different numbers of nucleotides in the variable loop.
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Multiple mechanisms are employed to change the fate of a mature tRNA. Once generated, mature transfer RNAs (tRNAs) can be prevented from functioning in translation via multiple mechanisms. tRNAs can be imported and selectively retained in the nucleus, cleaved to generate a variety of small RNAs, or marked for degradation via the post‐transcriptional addition of 3′ terminal tails.
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Proofreading by the CCA‐adding enzyme determines transfer RNA (tRNA) fate. A primary tRNA transcript is first processed at its 5′ and 3′ ends prior to recognition by the CCA‐adding enzyme. For simplicity, the D and anticodon arms are not shown in subsequent steps. Only the head and neck domains, which comprise the catalytic center, are shown for the CCA‐adding enzyme. After the addition of CCA, nucleotide binding triggers closure of the head domain and either disassociation of structurally stable tRNAs or refolding of structurally unstable tRNAs. While transcripts ending in CCA can be aminoacylated and function in translation, transcripts ending in CCACCA are recognized for degradation. Additional details for each step are provided in the text.
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CCA or CCACCA is specifically added to the 3′ ends of transfer RNA (tRNA)‐like transcripts. (a) Structures of mouse mascRNA as well as the mouse and human homologs of the MEN β tRNA‐like small RNA are shown. Nucleotides added post‐transcriptionally by the CCA‐adding enzyme are in blue. A sequence alignment between mouse mascRNA and the mouse MEN β tRNA‐like small RNA is shown in the middle. (b) In stark contrast to the mouse and human MEN β homologs, the top of the acceptor stem of the Rhesus monkey MEN β homolog is significantly more stable, resulting in CCA addition.
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Transfer RNAs (tRNAs) are highly modified post‐transcriptionally. Yeast tRNASer(CGA), which is commonly modified at 11 positions, is shown as an example. When yeast are grown at high temperatures, tRNASer(CGA) is degraded by the rapid tRNA decay pathway if ac4C12 and Um44 are absent owing to deletion of Tan1, a co‐activator of Kre33, and Trm44. Structural instability in the acceptor and TψC stems is highlighted.
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Maturation of transfer RNAs (tRNAs). Once transcribed, tRNAs are sequentially processed at their 5′ and 3′ ends to generate a mature tRNA that can be charged with an amino acid. While the 5′ leader sequence is almost universally cleaved off by the endonuclease RNase P, multiple mechanisms have been reported for tRNA 3′‐end processing. In humans, the endonuclease RNase Z cleaves downstream of the unpaired discriminator base, releasing the 3′ trailer sequence. Bacteria instead generally remove the 3′ trailer by trimming using 3′→5′ exonucleases (not shown). In humans and all other species that do not encode CCA on their tRNAs, CCA is then post‐transcriptionally added by the CCA‐adding enzyme to generate the amino acid attachment site.
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Opposing transfer RNA (tRNA) signatures in proliferating versus differentiated cells. A continuous spectrum of tRNA pools is observed in human cells depending on the cell's proliferative status. As differentiated or arrested cells begin to proliferate, a gradual transition in tRNA expression is observed toward the proliferation tRNA signature. Similarly, differentiation causes the tRNA pool to change in the opposite direction toward the differentiation tRNA signature. For many amino acids, there is at least one codon that is preferentially used in proliferation‐related genes and at least one distinct codon in differentiation‐related genes. For example, tRNAArg(ACG) and tRNAArg(CCG) are predominately expressed in differentiated cells, whereas tRNAArg(TCG) and tRNAArg(TCT) are more abundantly expressed in proliferating cells.
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Translation > Translation Regulation
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Processing > tRNA Processing

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