DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis.
The presence of multiple copies of the major replicative DNA polymerase (DnaE) in some organisms, including important pathogens and symbionts, has remained an unresolved enigma. We postulated that one copy might participate in error-prone DNA repair synthesis. We found that UV irradiation of Mycobacterium tuberculosis results in increased mutation frequency in the surviving fraction. We identified dnaE2 as a gene that is upregulated in vitro by several DNA damaging agents, as well as during infection of mice. Loss of this protein reduces both survival of the bacillus after UV irradiation and the virulence of the organism in mice. Our data suggest that DnaE2, and not a member of the Y family of error-prone DNA polymerases, is the primary mediator of survival through inducible mutagenesis and can contribute directly to the emergence of drug resistance in vivo. These results may indicate a potential new target for therapeutic intervention.
Boshoff
Helena I M
HI
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook II, 12441 Parklawn Drive, Rockville, MD 20852, USA.
Reed
Michael B
MB
Barry
Clifton E
CE
Mizrahi
Valerie
V
D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D016680:Genome, Bacterial; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics*; D018088:Tuberculosis, Multidrug-Resistant / Q000201:enzymology* / Q000235:genetics*
D004259:DNA-Directed DNA Polymerase