Gladys Mirey - Vendredi 26 janvier 2018 14h
Auditorium - Bât. 442 - Séminaire Micalis
Cytolethal Distending Toxin : mécanismes d’action d’une génotoxine bactérienne et perspectives
Toxalim INRA, UMR 1331, Toulouse
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, we showed that other DNA lesions preceded DSB formation. We developed a proliferation assay using human cell lines specifically depleted in each repair pathway and showed that impairment of single-strand break repair, but not nucleotide excision repair, sensitizes cells to CDT. We also documented the role of the replicative stress response and the involvement of the Fanconi Anemia repair pathway in response to CDT.
As CDT could promote malignant transformation, we also investigated the cellular outcomes induced by acute and chronic exposures to E. coli CDT in normal human colon epithelial cells (HCECs). We conducted a comparative study between isogenic derivatives cell lines of the normal HCECs in order to mimic mutation of genes in colorectal cancer. Compared to normal HCECs, the precancerous derivatives exhibit hallmarks of malignant transformation after a chronic exposure to CDT. HCECs defective in APC and p53 showed enhanced anchorage independent growth and genetic instability, assessed by the micronucleus formation assay. In contrast, the ability to grow independently of anchorage was not impacted by CDT chronic exposure in KRASV12 HCECs, but micronucleus formation is dramatically increased. Thus, CDT does not initiate CRC by itself, but may have promoting effects in premalignant HCECs, involving different mechanisms in function of the genetic alterations associated to CRC.
In conclusion, our work indicates that cellular survival to CDT-induced DNA damage involves different repair pathways. This reinforces a model where CDT-related genotoxicity primarily involves single-strand breaks rather than DSBs, underlining the importance of cell proliferation during CDT intoxication and pathogenicity.
Vendredi 26 janvier 2018
Auditorium - Bât. 442
INRA, Jouy en Josas
Invitée par Hélène Bierne