Open AccessThe Haemophilus ducreyi cytolethal distending toxin activates sensors of DNA damage and repair complexes in proliferating and non‐proliferating cells
Author(s) -
Li LiQi,
Sharipo Anatoly,
ChavesOlarte Esteban,
Masucci Maria G.,
Levitsky Victor,
Thelestam Monica,
Frisan Teresa
Publication year - 2002
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1046/j.1462-5822.2002.00174.x
Subject(s) - cytolethal distending toxin , biology , dna damage , microbiology and biotechnology , g2 m dna damage checkpoint , proliferating cell nuclear antigen , checkpoint kinase 2 , dna repair , chek1 , phosphorylation , cell cycle checkpoint , apoptosis , cell growth , cell cycle , dna , protein kinase a , genetics , toxin , protein serine threonine kinases , microbial toxins
Summary Cytolethal distending toxins (CDTs) block proliferation of mammalian cells by activating DNA damage‐induced checkpoint responses. We demonstrate that the Haemophilus ducreyi CDT (HdCDT) induces phosphorylation of the histone H2AX as early as 1 h after intoxication and re‐localization of the DNA repair complex Mre11 in HeLa cells with kinetics similar to those observed upon ionizing radiation. Early phosphorylation of H2AX was dependent on a functional Ataxia Telangiectasia mutated (ATM) kinase. Microinjection of a His‐tagged HdCdtB subunit, homologous to the mammalian DNase I, was sufficient to induce re‐localization of the Mre11 complex 1 h post treatment. However, the enzymatic potency was much lower than that exerted by bovine DNase I, which caused marked chromatin changes at 10 6 times lower concentrations than HdCdtB. H2AX phosphorylation and Mre11 re‐localization were induced also in HdCDT‐treated, non‐proliferating dendritic cells (DCs) in a differentiation dependent manner, and resulted in cell death. The data highlight several novel aspects of CDTs biology. We demonstrate that the toxin activates DNA damage‐associated molecules in an ATM‐dependent manner, both in proliferating and non‐proliferating cells, acting as other DNA damaging agents. Induction of apoptotic death of immature DCs by HdCDT may represent a previously unknown mechanism of immune evasion by CDT‐producing microbes.