Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli
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Author(s)
Davies, Bryan W.
Kohanski, Michael A.
Simmons, Lyle A.
Winkler, Jonathan A.
Collins, James J.
Walker, Graham C.
Date Issued
December 2009
Journal
Molecular Cell
Publisher
Elsevier B.V.
Citation
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.
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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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.
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DOI of Published Version
https://doi.org/10.1016/j.molcel.2009.11.024
