A new mode of action of a bacterial genotoxin: the cytolethal distending toxin

National audience; The Cytolethal Distending Toxin (CDT) is a virulence factor produced by many pathogenic bacteria like Escherichia coli, Salmonella typhi, etc. The CDT production allows bacteria to persistently colonize the body and to evade the immune system. Moreover, the production of CDT by Helicobacter hepaticus leads to the development of pre-cancerous lesions liver, in a rat model. It is essential to understand effects of CDT on our body and so characterize the effect of CDT on eukaryotic cells. Into cells, CDT induces DNA double-stranded breaks (DSB), leading to a block of the proliferation and to cell death. However, we have shown that at doses 1000 times lower than those used in the literature, CDT induces single-strand breaks, and after replication, this damages will degenerate into DSB. The importance of the replication passage suggests that proliferating cells are more sensitive to CDT than quiescent cells. Some bacteria producing CDT colonize the intestinal epithelium, where some cells proliferate a lot. This raises the question of the involvement of CDT in the carcinogenesis of this epithelium. To better characterize the effect of CDT on our DNA and especially during replication, we are studying the catalytic activity of CDT and its interaction with the DNA.