Inhibition of bacterial DNA replication by zinc mobilization during nitrosative stress.
Phagocytic cells inhibit the growth of intracellular pathogens by producing nitric oxide (NO). NO causes cell filamentation, induction of the SOS response, and DNA replication arrest in the Gram-negative bacterium Salmonella enterica. NO also induces double-stranded chromosomal breaks in replication-arrested Salmonella lacking a functional RecBCD exonuclease. This DNA damage depends on actions of additional DNA repair proteins, the RecG helicase, and RuvC endonuclease. Introduction of a recG mutation restores both resistance to NO and the ability of an attenuated recBC mutant Salmonella strain to cause lethal infection in mice, demonstrating that bacterial DNA replication is inhibited during host-pathogen interactions. Inhibition of DNA replication during nitrosative stress is invariably accompanied by zinc mobilization, implicating DNA-binding zinc metalloproteins as critical targets of NO-related antimicrobial activity.
Schapiro
Jeffrey M
JM
Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195-7242, USA.
Libby
Stephen J
SJ
Fang
Ferric C
FC
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D019457:Chromosome Breakage; D002876:Chromosomes, Bacterial / Q000235:genetics; D004249:DNA Damage; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D004269:DNA, Bacterial / Q000096:biosynthesis*; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins; D043211:Exodeoxyribonuclease V; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010587:Phagocytosis / Q000502:physiology*; D026403:S-Nitrosothiols / Q000378:metabolism; D019779:Salmonella enterica / Q000235:genetics* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D001426:Bacterial Proteins; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D008562:Membrane Glycoproteins; D026403:S-Nitrosothiols; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; D043211:Exodeoxyribonuclease V; C468322:exodeoxyribonuclease V, E coli; D004265:DNA Helicases; D015032:Zinc