opportunistic pathogen Pseudomonas aeruginosa activates the DNA double-strand break signaling and repair pathway in infected cells

• Published in: Cellular and molecular life sciences : CMLS 2013-11, Vol.70 (22), p.4385-4397
• Main Authors: Elsen, Sylvie, Collin-Faure, Véronique, Gidrol, Xavier, Lemercier, Claudie
• Format: Article
• Language: English
• Subjects: ADP Ribose Transferases; ADP Ribose Transferases - metabolism; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins; Ataxia Telangiectasia Mutated Proteins - metabolism; Bacterial infections; Bacterial Proteins; Bacterial Proteins - metabolism; Bacterial Toxins; Bacterial Toxins - metabolism; Biochemistry; Biochemistry, Molecular Biology; Biomedical and Life Sciences; Biomedicine; Cancer; carcinogenicity; Cell Biology; Cell Line, Tumor; Cellular Biology; Chromosomal Instability; cystic fibrosis; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA Repair; drugs; E coli; epithelial cells; equipment maintenance and repair; Escherichia coli; eukaryotic cells; gene deletion; genetic markers; genome; genotoxicity; Helicobacter pylori; Histones; Histones - metabolism; HL-60 Cells; Human health and pathology; Humans; infection; Infectious diseases; Intracellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins - metabolism; Irradiation; JNK Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases - metabolism; kinases; Life Sciences; mammals; Microbiology and Parasitology; Mutagenesis; Nosocomial infection; Pathogens; patients; Phosphorylation; phosphotransferases (kinases); Pseudomonas aeruginosa; Pseudomonas aeruginosa - metabolism; Research Article; Signal Transduction; Toxins; Tumor Suppressor p53-Binding Protein 1
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-013-1392-3

Highly hazardous DNA double-strand breaks can be induced in eukaryotic cells by a number of agents including pathogenic bacterial strains. We have investigated the genotoxic potential of Pseudomonas aeruginosa, an opportunistic pathogen causing devastating nosocomial infections in cystic fibrosis or immunocompromised patients. Our data revealed that infection of immune or epithelial cells by P. aeruginosa triggered DNA strand breaks and phosphorylation of histone H2AX (γH2AX), a marker of DNA double-strand breaks. Moreover, it induced formation of discrete nuclear repair foci similar to gamma-irradiation-induced foci, and containing γH2AX and 53BP1, an adaptor protein mediating the DNA-damage response pathway. Gene deletion, mutagenesis, and complementation in P. aeruginosa identified ExoS bacterial toxin as the major factor involved in γH2AX induction. Chemical inhibition of several kinases known to phosphorylate H2AX demonstrated that Ataxia Telangiectasia Mutated (ATM) was the principal kinase in P. aeruginosa-induced H2AX phosphorylation. Finally, infection led to ATM kinase activation by an auto-phosphorylation mechanism. Together, these data show for the first time that infection by P. aeruginosa activates the DNA double-strand break repair machinery of the host cells. This novel information sheds new light on the consequences of P. aeruginosa infection in mammalian cells. As pathogenic Escherichia coli or carcinogenic Helicobacter pylori can alter genome integrity through DNA double-strand breaks, leading to chromosomal instability and eventually cancer, our findings highlight possible new routes for further investigations of P. aeruginosa in cancer biology and they identify ATM as a potential target molecule for drug design.