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 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.
Davies
Bryan W
BW
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Kohanski
Michael A
MA
Simmons
Lyle A
LA
Winkler
Jonathan A
JA
Collins
James J
JJ
Walker
Graham C
GC
D017209:Apoptosis / Q000187:drug effects*; D001427:Bacterial Toxins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D004722:Endoribonucleases / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D029968:Escherichia coli Proteins / Q000378:metabolism / Q000502:physiology; D016680:Genome, Bacterial; D006918:Hydroxyurea / Q000494:pharmacology*; D008954:Models, Biological; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D051841:Transcription Factor RelB
D001427:Bacterial Toxins; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D006918:Hydroxyurea; D013481:Superoxides; C422954:MazE protein, E coli; C422955:MazF protein, E coli; C465567:RelB protein, E coli; D051841:Transcription Factor RelB; C465566:RelE protein, E coli