Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli
Hydroxyurea (HU) specifically inhibits class I ribonucleotide reductase (RNR), depleting dNTP pools and leading to replication fork arrest. Although HU inhibition of RNR is well recognized, the mechanism by which it leads to cell death remains unknown. To investigate the mechanism of HU-induced cell...
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| Aineistotyyppi: | Artikkeli |
| Kieli: | en_US |
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Elsevier B.V.
2014
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| Linkit: | http://hdl.handle.net/1721.1/85546 https://orcid.org/0000-0001-7243-8261 |
| _version_ | 1826198255588868096 |
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| author | Davies, Bryan W. Kohanski, Michael A. Simmons, Lyle A. Winkler, Jonathan A. Collins, James J. Walker, Graham C. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Davies, Bryan W. Kohanski, Michael A. Simmons, Lyle A. Winkler, Jonathan A. Collins, James J. Walker, Graham C. |
| author_sort | Davies, Bryan W. |
| collection | MIT |
| description | Hydroxyurea (HU) specifically inhibits class I ribonucleotide reductase (RNR), depleting dNTP pools and leading to replication fork arrest. Although HU inhibition of RNR is well recognized, the mechanism by which it leads to cell death remains unknown. To investigate the mechanism of HU-induced cell death, we used a systems-level approach to determine the genomic and physiological responses of E. coli to HU treatment. Our results suggest a model by which HU treatment rapidly induces a set of protective responses to manage genomic instability. Continued HU stress activates iron uptake and toxins MazF and RelE, whose activity causes the synthesis of incompletely translated proteins and stimulation of envelope stress responses. These effects alter the properties of one of the cell's terminal cytochrome oxidases, causing an increase in superoxide production. The increased superoxide production, together with the increased iron uptake, fuels the formation of hydroxyl radicals that contribute to HU-induced cell death. |
| first_indexed | 2024-09-23T11:01:50Z |
| format | Article |
| id | mit-1721.1/85546 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:01:50Z |
| publishDate | 2014 |
| publisher | Elsevier B.V. |
| record_format | dspace |
| spelling | mit-1721.1/855462022-09-27T16:39:09Z Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli Davies, Bryan W. Kohanski, Michael A. Simmons, Lyle A. Winkler, Jonathan A. Collins, James J. Walker, Graham C. Massachusetts Institute of Technology. Department of Biology Davies, Bryan W. Simmons, Lyle A. Walker, Graham C. Hydroxyurea (HU) specifically inhibits class I ribonucleotide reductase (RNR), depleting dNTP pools and leading to replication fork arrest. Although HU inhibition of RNR is well recognized, the mechanism by which it leads to cell death remains unknown. To investigate the mechanism of HU-induced cell death, we used a systems-level approach to determine the genomic and physiological responses of E. coli to HU treatment. Our results suggest a model by which HU treatment rapidly induces a set of protective responses to manage genomic instability. Continued HU stress activates iron uptake and toxins MazF and RelE, whose activity causes the synthesis of incompletely translated proteins and stimulation of envelope stress responses. These effects alter the properties of one of the cell's terminal cytochrome oxidases, causing an increase in superoxide production. The increased superoxide production, together with the increased iron uptake, fuels the formation of hydroxyl radicals that contribute to HU-induced cell death. National Institutes of Health (U.S.) (grant GM31030) National Institutes of Health (U.S.) (grant CA21615-27) National Institutes of Health (U.S.) (grant DP10D00364) Howard Hughes Medical Institute National Science Foundation (U.S.) (FIBR program) Natural Sciences and Engineering Research Council of Canada (Graduate scholarship) University of Michigan (Start-up funds) National Cancer Institute (U.S.) (postdoctoral fellowship) Massachusetts Institute of Technology. Center for Environmental Health Sciences National Institute of Environmental Health Sciences (Grant P30 ES00210) 2014-03-06T19:23:43Z 2014-03-06T19:23:43Z 2009-12 2009-07 Article http://purl.org/eprint/type/JournalArticle 10972765 http://hdl.handle.net/1721.1/85546 Davies, Bryan W., Michael A. Kohanski, Lyle A. Simmons, Jonathan A. Winkler, James J. Collins, and Graham C. Walker. “Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia Coli.” Molecular Cell 36, no. 5 (December 2009): 845–860. https://orcid.org/0000-0001-7243-8261 en_US http://dx.doi.org/10.1016/j.molcel.2009.11.024 Molecular Cell 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 Elsevier B.V. Elsevier Open Archive |
| spellingShingle | Davies, Bryan W. Kohanski, Michael A. Simmons, Lyle A. Winkler, Jonathan A. Collins, James J. Walker, Graham C. Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli |
| title | Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli |
| title_full | Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli |
| title_fullStr | Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli |
| title_full_unstemmed | Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli |
| title_short | Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli |
| title_sort | hydroxyurea induces hydroxyl radical mediated cell death in escherichia coli |
| url | http://hdl.handle.net/1721.1/85546 https://orcid.org/0000-0001-7243-8261 |
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