Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability
Genomic modification by sulfur in the form of phosphorothioate (PT) is widespread among prokaryotes, including human pathogens. Apart from its physiological functions, PT sulfur has redox and nucleophilic properties that suggest effects on bacterial fitness in stressful environments. Here we show th...
| Main Authors: | , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2018
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| Online Access: | http://hdl.handle.net/1721.1/117596 https://orcid.org/0000-0003-3224-7502 https://orcid.org/0000-0003-1615-1578 https://orcid.org/0000-0003-0011-3067 |
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| author | You, Delin Kellner, Stefanie M DeMott, Michael S Cheng, Ching Pin Russell, Brandon S Cao, Bo Dedon, Peter C |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering You, Delin Kellner, Stefanie M DeMott, Michael S Cheng, Ching Pin Russell, Brandon S Cao, Bo Dedon, Peter C |
| author_sort | You, Delin |
| collection | MIT |
| description | Genomic modification by sulfur in the form of phosphorothioate (PT) is widespread among prokaryotes, including human pathogens. Apart from its physiological functions, PT sulfur has redox and nucleophilic properties that suggest effects on bacterial fitness in stressful environments. Here we show that PTs are dynamic and labile DNA modifications that cause genomic instability during oxidative stress. In experiments involving isotopic labeling coupled with mass spectrometry, we observed sulfur replacement in PTs at a rate of ∼2% h-1in unstressed Escherichia coli and Salmonella enterica. Whereas PT levels were unaffected by exposure to hydrogen peroxide (H2O2) or hypochlorous acid (HOCl), PT turnover increased to 3.8-10% h1after HOCl treatment and was unchanged by H2O2, consistent with the repair of HOCl-induced sulfur damage. PT-dependent sensitivity to HOCl extended to cytotoxicity and DNA strand breaks, which occurred at HOCl doses that were orders of magnitude lower than the corresponding doses of H2O2. The genotoxicity of HOCl in PT-containing bacteria suggests reduced fitness in competition with HOCl-producing organisms and during infections in humans. |
| first_indexed | 2024-09-23T14:47:13Z |
| format | Article |
| id | mit-1721.1/117596 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:47:13Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1175962022-09-29T10:33:19Z Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability You, Delin Kellner, Stefanie M DeMott, Michael S Cheng, Ching Pin Russell, Brandon S Cao, Bo Dedon, Peter C Massachusetts Institute of Technology. Department of Biological Engineering Kellner, Stefanie M DeMott, Michael S Cheng, Ching Pin Russell, Brandon S Cao, Bo Dedon, Peter C Genomic modification by sulfur in the form of phosphorothioate (PT) is widespread among prokaryotes, including human pathogens. Apart from its physiological functions, PT sulfur has redox and nucleophilic properties that suggest effects on bacterial fitness in stressful environments. Here we show that PTs are dynamic and labile DNA modifications that cause genomic instability during oxidative stress. In experiments involving isotopic labeling coupled with mass spectrometry, we observed sulfur replacement in PTs at a rate of ∼2% h-1in unstressed Escherichia coli and Salmonella enterica. Whereas PT levels were unaffected by exposure to hydrogen peroxide (H2O2) or hypochlorous acid (HOCl), PT turnover increased to 3.8-10% h1after HOCl treatment and was unchanged by H2O2, consistent with the repair of HOCl-induced sulfur damage. PT-dependent sensitivity to HOCl extended to cytotoxicity and DNA strand breaks, which occurred at HOCl doses that were orders of magnitude lower than the corresponding doses of H2O2. The genotoxicity of HOCl in PT-containing bacteria suggests reduced fitness in competition with HOCl-producing organisms and during infections in humans. National Science Foundation (U.S.) (Grant CHE-1019990) National Institute of Environmental Health Sciences (Grant ES002109) National Institute of Allergy and Infectious Diseases (U.S.) (Grant AI112711) 2018-08-28T18:07:26Z 2018-08-28T18:07:26Z 2017-06 2016-06 2018-08-28T16:48:16Z Article http://purl.org/eprint/type/JournalArticle 1552-4450 1552-4469 http://hdl.handle.net/1721.1/117596 Kellner, Stefanie et al. “Oxidation of Phosphorothioate DNA Modifications Leads to Lethal Genomic Instability.” Nature Chemical Biology 13, 8 (June 2017): 888–894 © 2017 Nature Publishing Group https://orcid.org/0000-0003-3224-7502 https://orcid.org/0000-0003-1615-1578 https://orcid.org/0000-0003-0011-3067 http://dx.doi.org/10.1038/NCHEMBIO.2407 Nature Chemical Biology 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 Nature Publishing Group PMC |
| spellingShingle | You, Delin Kellner, Stefanie M DeMott, Michael S Cheng, Ching Pin Russell, Brandon S Cao, Bo Dedon, Peter C Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability |
| title | Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability |
| title_full | Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability |
| title_fullStr | Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability |
| title_full_unstemmed | Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability |
| title_short | Oxidation of phosphorothioate DNA modifications leads to lethal genomic instability |
| title_sort | oxidation of phosphorothioate dna modifications leads to lethal genomic instability |
| url | http://hdl.handle.net/1721.1/117596 https://orcid.org/0000-0003-3224-7502 https://orcid.org/0000-0003-1615-1578 https://orcid.org/0000-0003-0011-3067 |
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