Cytolethal distending toxin (CDT) is a radiomimetic agent and induces persistent levels of DNA double-strand breaks in human fibroblasts

Fahrer, Jörg; Huelsenbeck, Johannes; Jaurich, Henriette; Dörsam, Bastian; Frisan, Teresa; Eich, Marcus; Roos, Wynand P.; Kaina, Bernd; Fritz, Gerhard

doi:10.1016/j.dnarep.2014.03.002

Cited by 67 publications

(99 citation statements)

References 55 publications

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“…For example, Chlamydia trachomatis (33) and H. pylori (20) have been proposed to elicit dysregulated cell proliferation and mutagenic DNA damage, which in turn are thought to promote bacterial-induced carcinogenesis (33). Interestingly, H. hepaticus and Camplyobacter jejuni have been shown to produce cytolethal distending toxin (CDT), a carcinogenic tripartite protein that shows DNase activity in host nuclei (48)(49)(50). Given these examples of pathogens that have evolved mechanisms to induce DNA damage in mammalian cells, it seemed plausible that the host genome might be an intended target of S. pneumoniae.…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Rai

Parrish

Tay

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

102

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Streptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H 2 O 2 , plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H 2 O 2 , greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H 2 O 2 production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniaeinduced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.DNA damage | Streptococcus pneumoniae | hydrogen peroxide | γH2AX | Ku80

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Section: Discussionmentioning

confidence: 99%

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Rai

Parrish

Tay

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

102

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“…Afterwards samples were neutralized three times with 0.4 M Tris pH 7.5 and fixed in 100 % ethanol, air-dried and stained with 50 lg/ml propidium iodide. Results were microscopically analyzed by Olympus BX50 equipped with a ColorView camera (Olympus, Münster, Germany) [15]. As an output, 50 cells were scored using Comet IV software (Perceptive Instruments Ltd., Bury St Edmunds, UK) for each sample.…”

Section: Comet Assaymentioning

confidence: 99%

Nitroglycerin induces DNA damage and vascular cell death in the setting of nitrate tolerance

et al. 2016

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Nitroglycerin (GTN) and other organic nitrates are widely used vasodilators. Their side effects are development of nitrate tolerance and endothelial dysfunction. Given the potential of GTN to induce nitro-oxidative stress, we investigated the interaction between nitro-oxidative DNA damage and vascular dysfunction in experimental nitrate tolerance. Cultured endothelial hybridoma cells (EA.hy 926) and Wistar rats were treated with GTN (ex vivo: 10-1000 µM; in vivo: 10, 20 and 50 mg/kg/day for 3 days, s.c.). The level of DNA strand breaks, 8-oxoguanine and O (6)-methylguanine DNA adducts was determined by Comet assay, dot blot and immunohistochemistry. Vascular function was determined by isometric tension recording. DNA adducts and strand breaks were induced by GTN in cells in vitro in a concentration-dependent manner. GTN in vivo administration leads to endothelial dysfunction, nitrate tolerance, aortic and cardiac oxidative stress, formation of DNA adducts, stabilization of p53 and apoptotic death of vascular cells in a dose-dependent fashion. Mice lacking O (6)-methylguanine-DNA methyltransferase displayed more vascular O (6)-methylguanine adducts and oxidative stress under GTN therapy than wild-type mice. Although we were not able to prove a causal role of DNA damage in the etiology of nitrate tolerance, the finding of GTN-induced DNA damage such as the mutagenic and toxic adduct O (6)-methylguanine, and cell death supports the notion that GTN based therapy may provoke adverse side effects, including endothelial function. Further studies are warranted to clarify whether GTN pro-apoptotic effects are related to an impaired recovery of patients upon myocardial infarction.

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“…Up to now, no direct relation between CDT and cancer has been established. However, this toxin functions as a radiomimetic agent [40], triggering genomic instability and increasing mutation frequency, thereby supporting this possibility.…”

Section: Cdt Bacterial Dnase Targets the Eukaryotic Genomementioning

confidence: 96%

“…The microinjection of purified CDT in the cell nucleus triggers chromatin fragmentation [37]. In the presence of high doses of CDT, cells rapidly accumulate DSBs [36][37][38] with the concomitant formation of nuclear IRIF-like foci containing γH2AX and 53BP1 [37,39,40] and the strong activation of ATM-Chk2 and ATR-Chk1 signaling axes [40]. Depending on the type of cells challenged with CDT, the activation of the ATM-Chk2-p53 pathway results in G1 and /or G2 arrest, followed by cell death [41].…”

Section: Cdt Bacterial Dnase Targets the Eukaryotic Genomementioning

confidence: 99%

“…Epithelial or mesenchymal cells intoxicated with CDT die after several days, whereas more fragile lymphocytes die more rapidly through apoptosis [36]. In yeast, homologous recombination is the predominant DNA repair mechanism for protection against CDT-induced lesions [42], whereas in human cells, both HR and NHEJ repair pathways protect against CDT-induced DSBs [40]. At low doses, CDT primarily generates SSBs which are converted into DSBs during the S-phase [43,44].…”

Section: Cdt Bacterial Dnase Targets the Eukaryotic Genomementioning

confidence: 99%

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When our genome is targeted by pathogenic bacteria

Lemercier

2015

Cell. Mol. Life Sci.

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Eukaryotic cells repair thousands of lesions arising in the genome at each cell cycle. The most hazardous damage is likely DNA doublestrand breaks (DSB) that cleave the double helix backbone. DSBs occur naturally during T-cell receptor and immunoglobulin gene recombination in lymphocytes. DSBs can also arise as a consequence of exogenous stresses (e.g. ionizing irradiation, chemotherapeutic drugs, viruses) or oxidative processes. An increasing number of studies have reported that infection with pathogenic bacteria also alters the host genome, producing DSB and other modifications on DNA. This review focuses on recent data on bacteria-induced DNA damage and the known strategies used by these pathogens to maintain a physiological niche in the host. Even after DNA repair in infected cells, "scars" often remain on chromosomes and might generate genomic instability at the next cell division. Chronic inflammation in tissue, combined with infection and DNA damage, can give rise to genomic instability and eventually cancer. A functional link between the DNA damage response and the innate immune response has been recently established. Pathogenic bacteria also highjack the host cell cycle, often acting on the stability of the master regulator p53, or dampen the DNA damage response to support bacterial replication in an appropriate reservoir. Except in a few cases, the molecular mechanisms responsible for DNA lesions are poorly understood, although ROS release during infection is a serious candidate for generating DNA breaks. Thus, chronic or repetitive infections with genotoxic bacteria represent a common source of DNA lesions that compromise host genome integrity.

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Cytolethal distending toxin (CDT) is a radiomimetic agent and induces persistent levels of DNA double-strand breaks in human fibroblasts

Cited by 67 publications

References 55 publications

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Nitroglycerin induces DNA damage and vascular cell death in the setting of nitrate tolerance

When our genome is targeted by pathogenic bacteria

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