Host DNA repair proteins in response to Pseudomonas aeruginosa in lung epithelial cells and in mice.
Although DNA repair proteins in bacteria are critical for pathogens' genome stability and for subverting the host defense, the role of host DNA repair proteins in response to bacterial infection is poorly defined. Here, we demonstrate, for the first time, that infection with the Gram-negative bacterium Pseudomonas aeruginosa significantly altered the expression and enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1) in lung epithelial cells. Downregulation of OGG1 by a small interfering RNA strategy resulted in severe DNA damage and cell death. In addition, acetylation of OGG1 is required for host responses to bacterial genotoxicity, as mutations of OGG1 acetylation sites increased Cockayne syndrome group B (CSB) protein expression. These results also indicate that CSB may be involved in DNA repair activity during infection. Furthermore, OGG1 knockout mice exhibited increased lung injury after infection with P. aeruginosa, as demonstrated by higher myeloperoxidase activity and lipid peroxidation. Together, our studies indicate that P. aeruginosa infection induces significant DNA damage in host cells and that DNA repair proteins play a critical role in the host response to P. aeruginosa infection, serving as promising targets for the treatment of this condition and perhaps more broadly Gram-negative bacterial infections.
Department of Biochemistry and Molecular Biology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA. min.wu@med.und.edu
Min
M
Wu
Huang
H
Huang
Weidong
W
Zhang
Shibichakravarthy
S
Kannan
Andrew
A
Weaver
Molynda
M
McKibben
Danielle
D
Herington
Huawei
H
Zeng
Hongwei
H
Gao
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D015227:Lipid Peroxidation; D008168:Lung / Q000166:cytology*; D051379:Mice; D009195:Peroxidase; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa
D009195:Peroxidase; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse