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Arsenic toxicity is regulated by queuine availability and oxidation- induced reprogramming of the human tRNA epitranscriptome

ABSTRACT: Cells respond to environmental stress by regulating gene expression at the level of both transcription and translation. The ~50 modified ribonucleotides of the human epitranscriptome contribute to the latter, with mounting evidence that dynamic regulation of tRNA wobble modifications leads to selective translation of stress response proteins from codon-biased genes. Here we show that the response of human HepG2 cells to arsenite exposure is regulated by the availability of queuine, a micronutrient and essential precursor to the wobble modification queuosine (Q) on tRNAs reading GUN codons. Among oxidizing and alkylating agents at equitoxic concentrations, arsenite exposure caused an oxidant-specific increase in Q that correlated with up-regulation of proteins from codon-biased genes involved in energy metabolism. Limiting queuine increased arsenite-induced cell death, altered translation, increased reactive oxygen species levels, and caused mitochondrial dysfunction. In addition to revealing a new epitranscriptomic facet of arsenite toxicity and response, our results highlight the mechanistic links between environmental exposures, stress tolerance, and micronutrients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205332 | GEO | 2022/06/03

REPOSITORIES: GEO

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Arsenic toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome

Project description:Cells respond to environmental stress by regulating gene expression at the level of both transcription and translation. The ~50 modified ribonucleotides of the human epitranscriptome contribute to the latter, with mounting evidence that dynamic regulation of tRNA wobble modifications leads to selective translation of stress response proteins from codon-biased genes. Here we show that the response of human HepG2 cells to arsenite exposure is regulated by the availability of queuine, a micronutrient and essential precursor to the wobble modification queuosine (Q) on tRNAs reading GUN codons. Among oxidizing and alkylating agents at equitoxic concentrations, arsenite exposure caused an oxidant-specific increase in Q that correlated with up-regulation of proteins from codon-biased genes involved in energy metabolism. Limiting queuine increased arsenite-induced cell death, altered translation, increased reactive oxygen species levels, and caused mitochondrial dysfunction. In addition to revealing a new epitranscriptomic facet of arsenite toxicity and response, our results highlight the mechanistic links between environmental exposures, stress tolerance, and micronutrients.

2022-08-27 | PXD030726 | Pride

Nutritional control of protein translation

Project description:Regulation of protein translation is a key feature of many biological processes. Global protein translation as well as translation at the codon level can be regulated by RNA modifications. These modifications are particularly enriched in tRNAs, where they represent an additional regulatory layer on top of the primary RNA sequence. In eukaryotes, levels of tRNA queuosinylation reflect the bioavailability of the precursor queuine, which is salvaged from the gut microbiota and absorbed in the intestine. We show here that reduced queuine supply results in a strong reduction of tRNA queuosinylation in various cultured human cell lines and mouse tissues. In addition, Dnmt2-dependent tRNA methylation is dynamically modulated by the presence or absence of queuine. Ribosome profiling showed that nutritionally determined queuosine-tRNA (Q-tRNA) levels control the translation speed of Q-tRNA decoded codons. Dysregulation of translation resulted in pronounced endoplasmic reticulum stress and activation of the unfolded protein response, which could be rescued by the addition of queuine. Together, these findings establish a direct link between nutrient availability and the decoding of the transcriptome, thus providing a new perspective in our understanding of translational regulation.

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Queuosine modification of tRNA-Tyr elicits translational reprogramming and enhances growth of Vibrio cholerae with aminoglycosides

Project description:Tgt is responsible for the queuosine (Q) modification of the guanine (G) in tRNAs with GUN anti-codon. We have previously identified tgt as being vital for growth in presence sub-lethal concentrations of aminoglycosides in Vibrio cholerae. Here we further explore the role of Q modification in translation fidelity and efficiency of codon decoding upon tobramycin exposure. We characterize the impact on codon decoding efficiency, the overall translation of the bacterial proteome, and the molecular mechanisms underlying the effects of Q modification in antibiotic stress response. Using molecular reporters, we show that Q modification impacts the efficiency of decoding at tyrosine TAT and TAC codons. Proteomics identify the anti-SoxR factor RsxA as better translated in the absence of tgt. RsxA displays a codon bias towards tyrosine TAT and its overabundance leads to decreased expression of genes belonging to SoxR oxidative stress regulon. We also identify conditions which regulate tgt expression. We propose that regulation of Q modification in response to environmental cues leads to translational reprogramming of genes bearing a biased tyrosine codon usage. In silico analysis further identifies candidate genes possibly subjected to such translational regulation, among which DNA repair factors. Such transcripts, which fit the definition of modification tunable transcripts, are plausibly central in the bacterial response to antibiotic stress.

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Project description:In most eukaryotes and bacteria, queuosine (Q) replaces the guanosine at the wobble position of tRNAs harboring a GUN anticodon. To faithfully detect Q-modification in RNAs from Schizosaccharomyces pombe and Shigella flexneri, Q-MaP-Seq was established and applied to tRNAs from S. pombe WT (AEP1) cells and Shigella flexneri WT cells and tgt∆ cells. Q-modification of in vitro-transcribed RNAs and RNAs isolated from S. pombe and S. flexneri followed by reverse transcription using the RT-active DNA polymerase variant RT-KTq I614Y and sequencing of unmodified compared to modified RNAs allowed identification of Q-sites within tRNAs.

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