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The bacterial cytolethal distending Toxin induces indirect double-strand breaks into eukaryotic cells

Abstract : The Cytolethal Distending Toxin (CDT) is produced by many pathogenic gram-minus bacteria (Escherichia coli, Helicobacter hepaticus, H. ducreyi...) colonizing the oral cavity, the intestinal tract, the liver, etc. Depending on the affected organs, these bacteria are responsible of different pathologies. In vivo, the production of CDT by Helicobacter hepaticus induces the development of liver tumor nodules, thus defining CDT as a potential carcinogen. Given the important role of the CDT toxin in the physiopathology of these bacteria, it is essential to accurately identify its mode of action. After the release by the bacteria, CDT enter into eukaryotic cells and reach the nucleus and the DNA. In human cells, CDT has been considered to induce DNA damages and more precisely DNA double-strand breaks. However, we recently showed that the type of DNA damage induced by CDT in human cells is dose and cell cycle dependent, leading to a more complex model than a typical double-strand breaks induction. In order to support DNA damages, eukaryotic cells have several DNA repair pathways. Depending on the type of DNA damage induced (single-strand break, DNA adducts, double-strand breaks, etc,.) the repair pathway activated will not be the same. To better understand the type of DNA damages induced by CDT, we studied repairs pathways involved and activated by human cells following a CDT intoxination. We have shown that pathways involved in the repair of single-strand breaks, lesions blocking the replication fork and double-strand breaks are essential for human cells survival after a CDT treatment. These results confirm our hypothesis that CDT induces in a first time single-strand breaks. During the S phase of the cell cycle, unrepaired damages will blocked the replication forks. Finally, this blockage generating high tensions, single-strand breaks will degenerated into double-strand breaks. Our work has allowed a better understanding of the activity of CDT expressing bacteria on eukaryotic cells, and highlights the potential impact of this bacteria on proliferating cells.
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Conference papers
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https://hal.inrae.fr/hal-02796083
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Submitted on : Friday, June 5, 2020 - 1:18:18 PM
Last modification on : Tuesday, October 19, 2021 - 2:24:44 PM

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  • HAL Id : hal-02796083, version 1
  • PRODINRA : 343107

Citation

Elisabeth Bezine, Julien Vignard, Marianne Chevalier, Elisa Boutet-Robinet, Bernard Salles, et al.. The bacterial cytolethal distending Toxin induces indirect double-strand breaks into eukaryotic cells. Journée de l’ecole Doctorale SEVAB, Mar 2015, Toulouse, France. ⟨hal-02796083⟩

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