The Haemophilus ducreyi cytolethal distending toxin activates sensors of DNA damage and repair complexes in proliferating and non‐proliferating cells
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...
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Veröffentlicht in: | Cellular microbiology 2002-02, Vol.4 (2), p.87-99 |
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Zusammenfassung: | 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 106 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. |
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ISSN: | 1462-5814 1462-5822 |
DOI: | 10.1046/j.1462-5822.2002.00174.x |