Cytolethal Distending Toxin (CDT) is a bacterial toxin that induces G2/M cell cycle arrest, cell distension, and/or apoptosis in mammalian cells. It is produced by several Gram-negative species and may contribute to their pathogenicity. The catalytic subunit, CdtB, has homology with DNaseI and may act as a genotoxin. However, the mechanism how CdtB leads to cell death is not yet clearly understood. Here we used yeast as a model to study the molecular pathways involved in the function of CdtB from Aggregatibacter actinomycetemcomitans (Aa), a cause of aggressive periodontitis. We show that AaCdtB expression induces S/G2 arrest and death in a DNase-catalytic residue and nuclear-localization dependent manner in haploid yeasts. Yeast strains defective in homologous recombination (HR) repair, but not other DNA repair pathways, are hypersensitive to AaCdtB, suggesting that HR is required for survival upon CdtB expression. In addition, yeast does not harbor the substrate for the other activity proposed for CdtB function, that is phosphatidylinositol-3,4,5-triphosphate phosphatase. Thus, these results suggest that direct DNA damaging activity alone is sufficient for CdtB toxicity. To investigate how CdtB induces cell death, we examined the effect of CdtB in yeast strains with mutations in apoptotic regulators. Our results suggest that yeast death occurs independently of the yeast metacaspase, YCA1, and Apoptosis Inducing Factor, AIF1, but is partially dependent on histone H2B serine 10 phosphorylation. Therefore, we report here the evidence that AaCdtB causes DNA damage that leads to non-apoptotic death in yeast, and the first mutation that confers resistance to CdtB.
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