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

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.