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
]
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
DrugTargetKindOrganismPharmacological ActionActions
HydroxyureaRibonucleoside-diphosphate reductase large subunitProteinHumans
Yes
Inhibitor
Details
Polypeptides
NameUniProt ID
Ferrichrome-iron receptorP06971Details
Iron(3+)-hydroxamate-binding protein FhuDP07822Details
Fe(3+) dicitrate transport protein FecAP13036Details
Ribonucleoside-diphosphate reductase 1 subunit betaP69924Details
DNA polymerase III subunit betaP0A988Details
Cell division protein ZipAP77173Details
Protein TonBP02929Details
DNA polymerase IVQ47155Details
Protein RecAP0A7G6Details