Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome
<jats:p>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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2023
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| Online Access: | https://hdl.handle.net/1721.1/147796 |
| _version_ | 1826192918802595840 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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 |
| author_sort | Huber, Sabrina M |
| collection | MIT |
| description | <jats:p>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.</jats:p> |
| first_indexed | 2024-09-23T09:30:51Z |
| format | Article |
| id | mit-1721.1/147796 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:30:51Z |
| publishDate | 2023 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1477962023-02-01T03:49:12Z Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome 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 Massachusetts Institute of Technology. Department of Biological Engineering <jats:p>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.</jats:p> 2023-01-31T14:48:13Z 2023-01-31T14:48:13Z 2022 2023-01-31T14:37:27Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147796 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). en 10.1073/PNAS.2123529119 Proceedings of the National Academy of Sciences of the United States of America Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | 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 Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome |
| title | Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome |
| title_full | Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome |
| title_fullStr | Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome |
| title_full_unstemmed | Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome |
| title_short | Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome |
| title_sort | arsenite toxicity is regulated by queuine availability and oxidation induced reprogramming of the human trna epitranscriptome |
| url | https://hdl.handle.net/1721.1/147796 |
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