title: Cell resistance to the Cytolethal Distending Toxin involves an association of DNA repair mechanisms.
abstract: The Cytolethal Distending Toxin (CDT), produced by many bacteria, has been associated with various diseases including cancer. CDT induces DNA double-strand breaks (DSBs), leading to cell death or mutagenesis if misrepaired. At low doses of CDT, other DNA lesions precede replication-dependent DSB formation, implying that non-DSB repair mechanisms may contribute to CDT cell resistance. To address this question, we developed a proliferation assay using human cell lines specifically depleted in each of the main DNA repair pathways. Here, we validate the involvement of the two major DSB repair mechanisms, Homologous Recombination and Non Homologous End Joining, in the management of CDT-induced lesions. We show that impairment of single-strand break repair (SSBR), but not nucleotide excision repair, sensitizes cells to CDT, and we explore the interplay of SSBR with the DSB repair mechanisms. Finally, we document the role of the replicative stress response and demonstrate the involvement of the Fanconi Anemia repair pathway in response to CDT. In conclusion, our work indicates that cellular survival to CDT-induced DNA damage involves different repair pathways, in particular SSBR. This reinforces a model where CDT-related genotoxicity primarily involves SSBs rather than DSBs, underlining the importance of cell proliferation during CDT intoxication and pathogenicity.
authors: INRA, UMR1331, Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France.|Université de Toulouse, Institut National Polytechnique de Toulouse, F-31030 Toulouse, France.
authors: Elisabeth
authors: E
authors: Bezine
authors: INRA, UMR1331, Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, F-31062 Toulouse, France.
authors: Yann
authors: Y
authors: Malaisé
authors: INRA, UMR1331, Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, F-31062 Toulouse, France.
authors: Aurore
authors: A
authors: Loeuillet
authors: INRA, UMR1331, Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France.
authors: Marianne
authors: M
authors: Chevalier
authors: INRA, UMR1331, Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, F-31062 Toulouse, France.
authors: Elisa
authors: E
authors: Boutet-Robinet
authors: INRA, UMR1331, Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, F-31062 Toulouse, France.
authors: Bernard
authors: B
authors: Salles
authors: INRA, UMR1331, Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France.|Université de Toulouse, Université Paul Sabatier, F-31062 Toulouse, France.
authors: Gladys
authors: G
authors: Mirey
authors: INRA, UMR1331, Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France.
authors: Julien
authors: J
authors: Vignard
mesh_terms: D001427:Bacterial Toxins / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D059766:DNA End-Joining Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D045325:HCT116 Cells; D006367:HeLa Cells; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans
chemical_list: D001427:Bacterial Toxins; C067044:cytolethal distending toxin