Mistranslation: from adaptations to applications

Hoffman, Kyle S.; O’Donoghue, Patrick; Brandl, Christopher J.

doi:10.1016/j.bbagen.2017.01.031

Cited by 15 publications

(14 citation statements)

References 191 publications

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“…In addition, cells have protein quality control mechanisms to cope with mis-made proteins resulting from mistranslation. These include the ubiquitin-proteasome system, autophagy, induction of the heat shock and unfolded protein responses, and the organization of aggregates into inclusion bodies (reviewed in Hoffman et al 2017b). When mistranslation reaches a threshold, protein quality control mechanisms no longer protect the cell.…”

Section: Introductionmentioning

confidence: 99%

The amino acid substitution affects cellular response to mistranslation

Berg

Zhu

Ruiz

et al. 2021

Preprint

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Mistranslation, the mis-incorporation of an amino acid not specified by the standard genetic code, occurs in all organisms. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. Interestingly, human genomes contain tRNA variants with the potential to mistranslate. Cells cope with increased mistranslation through multiple mechanisms, though high levels cause proteotoxic stress. The goal of this study was to compare the genetic interactions and the impact on transcriptome and cellular growth of two tRNA variants that mistranslate at a similar frequency but create different amino acid substitutions in Saccharomyces cerevisiae. One tRNA variant inserts alanine at proline codons whereas the other inserts serine for arginine. Both tRNAs decreased growth rate, with the effect being greater for arginine to serine than for proline to alanine. The tRNA that substituted serine for arginine resulted in a heat shock response. In contrast, heat shock response was minimal for proline to alanine substitution. Further demonstrating the significance of the amino acid substitution, transcriptome analysis identified unique up- and downregulated genes in response to each mistranslating tRNA. Number and extent of negative synthetic genetic interactions also differed depending upon type of mistranslation. Based on the unique responses observed for these mistranslating tRNAs, we predict that the potential of mistranslation to exacerbate diseases caused by proteotoxic stress depends on the tRNA variant. Furthermore, based on their unique transcriptomes and genetic interactions, different naturally occurring mistranslating tRNAs have the potential to negatively influence specific diseases.

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Section: Introductionmentioning

confidence: 99%

The amino acid substitution affects cellular response to mistranslation

Berg

Zhu

Ruiz

et al. 2021

Preprint

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“…Secondly, decoding at the ribosome ensures the correct pairing between a tRNA anticodon and the mRNA codon. Errors at either step can result in the incorporation of the wrong amino acid into the growing polypeptide chain, known as mistranslation [1].…”

Section: Introductionmentioning

confidence: 99%

Acceptor Stem Differences Contribute to Species-Specific Use of Yeast and Human tRNASer

Berg

Genereaux

Zhu

et al. 2018

Genes

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The molecular mechanisms of translation are highly conserved in all organisms indicative of a single evolutionary origin. This includes the molecular interactions of tRNAs with their cognate aminoacyl-tRNA synthetase, which must be precise to ensure the specificity of the process. For many tRNAs, the anticodon is a major component of the specificity. This is not the case for the aminoacylation of alanine and serine to their cognate tRNAs. Rather, aminoacylation relies on other features of the tRNA. For tRNASer, a key specificity feature is the variable arm, which is positioned between the anticodon arm and the T-arm. The variable arm is conserved from yeast to human. This work was initiated to determine if the structure/function of tRNASer has been conserved from Saccharomyces cerevisiae to human. We did this by detecting mistranslation in yeast cells with tRNASer derivatives having the UGA anticodon converted to UGG for proline. Despite being nearly identical in everything except the acceptor stem, human tRNASer is less active than yeast tRNASer. A chimeric tRNA with the human acceptor stem and other sequences from the yeast molecule acts similarly to the human tRNASer. The 3:70 base pair in the acceptor stem (C:G in yeast and A:U in humans) is a prime determinant of the specificity. Consistent with the functional difference of yeast and human tRNASer resulting from subtle changes in the specificity of their respective SerRS enzymes, the functionality of the human and chimeric tRNASerUGG molecules was enhanced when human SerRS was introduced into yeast. Residues in motif 2 of the aminoacylation domain of SerRS likely participated in the species-specific differences. Trp290 in yeast SerRS (Arg313 in humans) found in motif 2 is proximal to base 70 in models of the tRNA-synthetase interaction. Altering this motif 2 sequence of hSerRS to the yeast sequence decreases the activity of the human enzyme with human tRNASer, supporting the coadaptation of motif 2 loop–acceptor stem interactions.

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“…The selection relied on a stress-sensitive allele of the PIK kinase chaperon, Tti2. 11,19,20 The selection produced four independent strains with a single base mutation (C70U) in the acceptor stem of tRNA Pro , yielding a tRNA Pro with the essential G3: U70 identity element for alanyl-tRNA synthetase (AlaRS). Unlike many tRNA synthetases, AlaRS does not recognize the anticodon of its cognate tRNA (Fig.…”

Section: Introductionmentioning

confidence: 99%

Visualizing tRNA-dependent mistranslation in human cells

et al. 2017

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High-fidelity translation and a strictly accurate proteome were originally assumed as essential to life and cellular viability. Yet recent studies in bacteria and eukaryotic model organisms suggest that proteome-wide mistranslation can provide selective advantages and is tolerated in the cell at higher levels than previously thought (one error in 6.9 × 10 in yeast) with a limited impact on phenotype. Previously, we selected a tRNA containing a single mutation that induces mistranslation with alanine at proline codons in yeast. Yeast tolerate the mistranslation by inducing a heat-shock response and through the action of the proteasome. Here we found a homologous human tRNA (G3:U70) mutant that is not aminoacylated with proline, but is an efficient alanine acceptor. In live human cells, we visualized mistranslation using a green fluorescent protein reporter that fluoresces in response to mistranslation at proline codons. In agreement with measurements in yeast, quantitation based on the GFP reporter suggested a mistranslation rate of up to 2-5% in HEK 293 cells. Our findings suggest a stress-dependent phenomenon where mistranslation levels increased during nutrient starvation. Human cells did not mount a detectable heat-shock response and tolerated this level of mistranslation without apparent impact on cell viability. Because humans encode ∼600 tRNA genes and the natural population has greater tRNA sequence diversity than previously appreciated, our data also demonstrate a cell-based screen with the potential to elucidate mutations in tRNAs that may contribute to or alleviate disease.

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Mistranslation: from adaptations to applications

Cited by 15 publications

References 191 publications

The amino acid substitution affects cellular response to mistranslation

The amino acid substitution affects cellular response to mistranslation

Acceptor Stem Differences Contribute to Species-Specific Use of Yeast and Human tRNASer

Visualizing tRNA-dependent mistranslation in human cells

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