Hydroxyurea induces hydroxyl radical-mediated cell death in Escherichia coli.

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Davies BW, Kohanski MA, Simmons LA, Winkler JA, Collins JJ, Walker GC

Hydroxyurea induces hydroxyl radical-mediated cell death in Escherichia coli.

Mol Cell. 2009 Dec 11;36(5):845-60. doi: 10.1016/j.molcel.2009.11.024.

PubMed ID

20005847 [View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Hydroxyurea	Ribonucleoside-diphosphate reductase large subunit	Protein	Humans	Yes	Inhibitor	Details

Polypeptides

Name	UniProt ID
Ferrichrome-iron receptor	P06971	Details
Iron(3+)-hydroxamate-binding protein FhuD	P07822	Details
Fe(3+) dicitrate transport protein FecA	P13036	Details
Ribonucleoside-diphosphate reductase 1 subunit beta	P69924	Details
DNA polymerase III subunit beta	P0A988	Details
Cell division protein ZipA	P77173	Details
Protein TonB	P02929	Details
DNA polymerase IV	Q47155	Details
Protein RecA	P0A7G6	Details