title: Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response.
abstract: Epidemiological evidence links chronic bacterial infections to the increased incidence of certain types of cancer but the molecular mechanisms by which bacteria contribute to tumour initiation and progression are still poorly characterized. Here we show that chronic exposure to the genotoxin cytolethal distending toxin (CDT) of Gram-negative bacteria promotes genomic instability and acquisition of phenotypic properties of malignancy in fibroblasts and colon epithelial cells. Cells grown for more than 30 weeks in the presence of sublethal doses of CDT showed increased mutation frequency, and accumulation of chromatin and chromosomal aberrations in the absence of significant alterations of cell cycle distribution, decreased viability or senescence. Cell survival was dependent on sustained activity of the p38 MAP kinase. The ongoing genomic instability was associated with impaired activation of the DNA damage response and failure to efficiently activate cell cycle checkpoints upon exposure to genotoxic stress. Independently selected sublines showed enhanced anchorage-independent growth as assessed by the formation of colonies in semisolid agarose. These findings support the notion that chronic infection by CDT-producing bacteria may promote malignant transformation, and point to the impairment of cellular control mechanisms associated with the detection and repair of DNA damage as critical events in the process.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Guidi
authors.forename: Lina
authors.initials: L
authors.lastname: Guerra
authors.forename: Laura
authors.initials: L
authors.lastname: Levi
authors.forename: Bo
authors.initials: B
authors.lastname: Stenerlöw
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Christine
authors.initials: C
authors.lastname: Josenhans
authors.forename: Maria G
authors.initials: MG
authors.lastname: Masucci
authors.forename: Teresa
authors.initials: T
authors.lastname: Frisan
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D042822:Genomic Instability / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000472:pathogenicity*; D006801:Humans; D009153:Mutagens / Q000378:metabolism*; D051381:Rats
chemical_list: D001427:Bacterial Toxins; D009153:Mutagens; C067044:cytolethal distending toxin