Phenotypic suppression of nonsense mutants in yeast by aminoglycoside antibiotics

Palmer, Edward L.; Wilhelm, J.; Sherman, Fred

doi:10.1038/277148a0

Cited by 222 publications

(129 citation statements)

References 12 publications

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“…6D). This aminoglycoside antibiotic decreases the translational accuracy by stimulating the stable association of near-cognate tRNA to the ribosome (28)(29)(30). Our data show that its effect is additive to the presence of unmodified tRNA, and they provide indirect evidence supporting the role of the modification in preventing misreading.…”

Section: Resultssupporting

confidence: 51%

The conserved Wobble uridine tRNA thiolase Ctu1–Ctu2 is required to maintain genome integrity

Dewez

Bauer

Dieu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

131

153

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Modified nucleosides close to the anticodon are important for the proper decoding of mRNA by the ribosome. Particularly, the uridine at the first anticodon position (U34) of glutamate, lysine, and glutamine tRNAs is universally thiolated (S 2 U34), which is proposed to be crucial for both restriction of wobble in the corresponding split codon box and efficient codon-anticodon interaction. Here we show that the highly conserved complex Ctu1-Ctu2 (cytosolic thiouridylase) is responsible for the 2-thiolation of cytosolic tRNAs in the nematode and fission yeast. In both species, inactivation of the complex leads to loss of thiolation on tRNAs and to a thermosensitive decrease of viability associated with marked ploidy abnormalities and aberrant development. Increased level of the corresponding tRNAs suppresses the fission yeast defects, and our data suggest that these defects could result from both misreading and frame shifting during translation. Thus, a translation defect due to unmodified tRNAs results in severe genome instability.thiolation ͉ yeast

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Section: Resultssupporting

confidence: 51%

The conserved Wobble uridine tRNA thiolase Ctu1–Ctu2 is required to maintain genome integrity

Dewez

Bauer

Dieu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

131

153

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“…In yeast, a prion conformation of the termination factor eRF3 increases read-through of termination codons (8), and recent evidence from ribosome profiling in Drosophila suggests that a subset of mRNAs may be regulated by stop codon readthrough to control gene expression and protein function (9). Additionally, and central to the studies reported here, stop codon read-through is enhanced by certain ribosome-targeting pharmaceutical compounds, such as aminoglycoside antibiotics (10) or the small molecule ataluren (PTC124) (11).…”

mentioning

confidence: 78%

Cryptic MHC class I-binding peptides are revealed by aminoglycoside-induced stop codon read-through into the 3′ UTR

Goodenough

Robinson

Zook

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Aminoglycosides have been proposed as therapies for genetic disorders caused by nonsense mutations, because of their capacity to enhance translational read-through of premature termination codons (PTCs), thereby permitting expression of functional fulllength protein. However, a potential consequence of this strategy is the development of an autoimmune response to HLA-presented epitopes encoded downstream of the PTC or other stop codons. Using a recombinant virus-expression system in tissue culture and in mice, we demonstrate that gentamicin can induce expression and MHC class I presentation of a model epitope encoded downstream of a PTC at levels sufficient to activate CD8 + T cells. The degree of read-through-derived peptide presentation varies with the sequence of the stop codon and +1 nucleotide. Additionally, we applied a mass spectrometry exploration of the HLA class I peptide repertoire of gentamicin-treated cells and identified multiple peptides derived from read-through of conventional stop codons. These results substantiate the possibility of self-reactivity to cryptic epitopes revealed by stop codon read-through therapies and potentially other therapeutic approaches involving compounds that alter translational fidelity.recoding | antigen presentation | autoimmunity

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“…Aminoglycoside antibiotics are active in the codonanticodon recognition of aminoacyl tRNAs during translation. 3,29,30 Significantly, 10-20% of the mutations identified in DMD and DMC are nonsense mutations resulting in premature stop codons. 18,21 In the analyses conducted to date, the role of the stop codon nucleotide context on readthrough efficiency has been investigated by directed mutagenesis of target sequences inserted into reporter genes.…”

Section: Discussionmentioning

confidence: 99%

Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment

et al. 2004

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The suppression levels induced by gentamicin on premature stop codons, caused by primary nonsense mutations found in muscular dystrophy patients, were assessed using a very sensitive dual reporter gene assay. Results show that: (i) the effect of gentamicin on readthrough is similar in cultured cells and in vivo in murine skeletal muscle; (ii) a wide variability of readthrough efficiency is obtained, depending on the mutation tested; (iii) due to the complexity of readthrough regulation, efficiency cannot be predicted by the nucleotide context of the stop codon; (iv) only a minority of premature stop codons found in patients show a significant level of readthrough, and would thus be amenable to this pharmacological treatment, given our present understanding of the problem. These results probably provide an explanation for the relative failure of clinical trials reported to date using gentamicin to treat diseases due to premature stop codons, and emphasize that preliminary assays in cell culture provide valuable information concerning the potential efficiency of pharmacological treatments.

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Phenotypic suppression of nonsense mutants in yeast by aminoglycoside antibiotics

Cited by 222 publications

References 12 publications

The conserved Wobble uridine tRNA thiolase Ctu1–Ctu2 is required to maintain genome integrity

The conserved Wobble uridine tRNA thiolase Ctu1–Ctu2 is required to maintain genome integrity

Cryptic MHC class I-binding peptides are revealed by aminoglycoside-induced stop codon read-through into the 3′ UTR

Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment

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