Cytolethal distending toxin demonstrates genotoxic activity in a yeast model.
Cytolethal distending toxins (CDTs) are multisubunit proteins produced by a variety of bacterial pathogens that cause enlargement, cell cycle arrest, and apoptosis in mammalian cells. While their function remains uncertain, recent studies suggest that they can act as intracellular DNases in mammalian cells. Here we establish a novel yeast model for understanding CDT-associated disease. Expression of the CdtB subunit in yeast causes a G2/M arrest, as seen in mammalian cells. CdtB toxicity is not circumvented in yeast genetically altered to lack DNA damage checkpoint control or that constitutively promote cell cycle progression via mutant Cdk1, because CdtB causes a permanent type of damage that results in loss of viability. Finally, we establish that CDTs are likely to be potent genotoxins, as indicated by in vivo degradation of chromosomal DNA associated with expression of CdtB-suggesting that the varied distribution of CDT in bacteria implicates many human pathogens as possessors of genotoxic activity.
Hassane
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DC
Department of Microbiology and Immunology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
Lee
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RB
Mendenhall
M D
MD
Pickett
C L
CL
D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism; D016123:Campylobacter jejuni / Q000378:metabolism*; D004249:DNA Damage; D004271:DNA, Fungal / Q000378:metabolism; D005656:Fungal Proteins / Q000187:drug effects / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins
D001427:Bacterial Toxins; D004271:DNA, Fungal; D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; C067044:cytolethal distending toxin; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D010727:Phosphoric Diester Hydrolases