Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes
Cells respond to stress by controlling gene expression at several levels, with little known about the role of translation. Here, we demonstrate a coordinated translational stress response system involving stress-specific reprogramming of tRNA wobble modifications that leads to selective translation...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Chemical Society
2017
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| Online Access: | http://hdl.handle.net/1721.1/106638 https://orcid.org/0000-0003-0011-3067 |
| _version_ | 1826191603240271872 |
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| author | Begley, Thomas J. Li, Fugen Chan, Clement T. Y. Deng, Wenjun DeMott, Michael S Babu, I. Ramesh Dedon, Peter C |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Begley, Thomas J. Li, Fugen Chan, Clement T. Y. Deng, Wenjun DeMott, Michael S Babu, I. Ramesh Dedon, Peter C |
| author_sort | Begley, Thomas J. |
| collection | MIT |
| description | Cells respond to stress by controlling gene expression at several levels, with little known about the role of translation. Here, we demonstrate a coordinated translational stress response system involving stress-specific reprogramming of tRNA wobble modifications that leads to selective translation of codon-biased mRNAs representing different classes of critical response proteins. In budding yeast exposed to four oxidants and five alkylating agents, tRNA modification patterns accurately distinguished among chemically similar stressors, with 14 modified ribonucleosides forming the basis for a data-driven model that predicts toxicant chemistry with >80% sensitivity and specificity. tRNA modification subpatterns also distinguish S[subscript N]1 from S[subscript N]2 alkylating agents, with S[subscript N]2-induced increases in m[superscript 3]C in tRNA mechanistically linked to selective translation of threonine-rich membrane proteins from genes enriched with ACC and ACT degenerate codons for threonine. These results establish tRNA modifications as predictive biomarkers of exposure and illustrate a novel regulatory mechanism for translational control of cell stress response. |
| first_indexed | 2024-09-23T08:58:29Z |
| format | Article |
| id | mit-1721.1/106638 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:58:29Z |
| publishDate | 2017 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | mit-1721.1/1066382022-09-30T12:33:33Z Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes Begley, Thomas J. Li, Fugen Chan, Clement T. Y. Deng, Wenjun DeMott, Michael S Babu, I. Ramesh Dedon, Peter C Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Chan, Clement T. Y. Deng, Wenjun DeMott, Michael S Babu, I. Ramesh Dedon, Peter C Cells respond to stress by controlling gene expression at several levels, with little known about the role of translation. Here, we demonstrate a coordinated translational stress response system involving stress-specific reprogramming of tRNA wobble modifications that leads to selective translation of codon-biased mRNAs representing different classes of critical response proteins. In budding yeast exposed to four oxidants and five alkylating agents, tRNA modification patterns accurately distinguished among chemically similar stressors, with 14 modified ribonucleosides forming the basis for a data-driven model that predicts toxicant chemistry with >80% sensitivity and specificity. tRNA modification subpatterns also distinguish S[subscript N]1 from S[subscript N]2 alkylating agents, with S[subscript N]2-induced increases in m[superscript 3]C in tRNA mechanistically linked to selective translation of threonine-rich membrane proteins from genes enriched with ACC and ACT degenerate codons for threonine. These results establish tRNA modifications as predictive biomarkers of exposure and illustrate a novel regulatory mechanism for translational control of cell stress response. National Science Foundation (U.S.) (Grant CHE-1308839) National Institute of Environmental Health Sciences (Grants ES002109 and ES017010) National Cancer Institute (U.S.) (Grant CA026731) Singapore-MIT Alliance for Research and Technology (SMART) 2017-01-26T19:19:06Z 2017-01-26T19:19:06Z 2015-03 2015-01 Article http://purl.org/eprint/type/JournalArticle 0893-228X 1520-5010 http://hdl.handle.net/1721.1/106638 Chan, Clement T. Y. et al. “Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes.” Chemical Research in Toxicology 28.5 (2015): 978–988. © 2015 American Chemical Society https://orcid.org/0000-0003-0011-3067 en_US http://dx.doi.org/10.1021/acs.chemrestox.5b00004 Chemical Research in Toxicology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society ACS |
| spellingShingle | Begley, Thomas J. Li, Fugen Chan, Clement T. Y. Deng, Wenjun DeMott, Michael S Babu, I. Ramesh Dedon, Peter C Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes |
| title | Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes |
| title_full | Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes |
| title_fullStr | Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes |
| title_full_unstemmed | Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes |
| title_short | Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes |
| title_sort | highly predictive reprogramming of trna modifications is linked to selective expression of codon biased genes |
| url | http://hdl.handle.net/1721.1/106638 https://orcid.org/0000-0003-0011-3067 |
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