Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome
Name
pnas.2123529119.pdf
Description
Published version
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2.64 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Huber, Sabrina M
Begley, Ulrike
Sarkar, Anwesha
Gasperi, William
Davis, Evan T
Surampudi, Vasudha
Lee, May
Melendez, J Andres
Dedon, Peter C
Begley, Thomas J
Date Issued
2022
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Citation
Huber, Sabrina M, Begley, Ulrike, Sarkar, Anwesha, Gasperi, William, Davis, Evan T et al. 2022. "Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome." Proceedings of the National Academy of Sciences of the United States of America, 119 (38).
Version
Final published version
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 transfer RNA (tRNA) wobble modifications leads to selective translation of stress response proteins from codon-biased genes. Here we show that the response of human hepatocellular carcinoma 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 demonstrating an epitranscriptomic facet of arsenite toxicity and response, our results highlight the links between environmental exposures, stress tolerance, RNA modifications, and micronutrients.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1073/PNAS.2123529119
