Cytolethal Distending Toxin Promotes Replicative Stress Leading to Genetic Instability Transmitted to Daughter Cells.

Autor:	Tremblay W; Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France., Mompart F; Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France., Lopez E; Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France., Quaranta M; IRSD, Université de Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France., Bergoglio V; MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France., Hashim S; Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France., Bonnet D; Department of Internale and Digestive Diseases, Pole Digestif, CHU Toulouse, Paul Sabatier University, Toulouse, France., Alric L; Department of Internale and Digestive Diseases, Pole Digestif, CHU Toulouse, Paul Sabatier University, Toulouse, France., Mas E; IRSD, Université de Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France.; Unité de Gastroentérologie, Hépatologie, Nutrition, Diabétologie et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, CHU de Toulouse, Toulouse, France., Trouche D; MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France., Vignard J; Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France., Ferrand A; IRSD, Université de Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France., Mirey G; Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France., Fernandez-Vidal A; Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.; MCD, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2021 May 07; Vol. 9, pp. 656795. Date of Electronic Publication: 2021 May 07 (Print Publication: 2021).
DOI:	10.3389/fcell.2021.656795
Abstrakt:	The cytolethal distending toxin (CDT) is produced by several Gram-negative pathogenic bacteria. In addition to inflammation, experimental evidences are in favor of a protumoral role of CDT-harboring bacteria such as Escherichia coli , Campylobacter jejuni , or Helicobacter hepaticus . CDT may contribute to cell transformation in vitro and carcinogenesis in mice models, through the genotoxic action of CdtB catalytic subunit. Here, we investigate the mechanism of action by which CDT leads to genetic instability in human cell lines and colorectal organoids from healthy patients' biopsies. We demonstrate that CDT holotoxin induces a replicative stress dependent on CdtB. The slowing down of DNA replication occurs mainly in late S phase, resulting in the expression of fragile sites and important chromosomic aberrations. These DNA abnormalities induced after CDT treatment are responsible for anaphase bridge formation in mitosis and interphase DNA bridge between daughter cells in G1 phase. Moreover, CDT-genotoxic potential preferentially affects human cycling cells compared to quiescent cells. Finally, the toxin induces nuclear distension associated to DNA damage in proliferating cells of human colorectal organoids, resulting in decreased growth. Our findings thus identify CDT as a bacterial virulence factor targeting proliferating cells, such as human colorectal progenitors or stem cells, inducing replicative stress and genetic instability transmitted to daughter cells that may therefore contribute to carcinogenesis. As some CDT-carrying bacterial strains were detected in patients with colorectal cancer, targeting these bacteria could be a promising therapeutic strategy. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Tremblay, Mompart, Lopez, Quaranta, Bergoglio, Hashim, Bonnet, Alric, Mas, Trouche, Vignard, Ferrand, Mirey and Fernandez-Vidal.)
Databáze:	MEDLINE
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