Genotoxicity of dietary, environmental and therapeutic topoisomerase II poisons is uniformly correlated to prolongation of enzyme DNA residence
| Autor: | Faiza Kalfalah, Simone Baechler, Doris Marko, Christian Mielke, Fritz Boege, Morten O. Christensen |
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| Rok vydání: | 2010 |
| Předmět: |
DNA damage
Genistein medicine.disease_cause Histones chemistry.chemical_compound Phenols Cell Line Tumor medicine Humans Topoisomerase II Inhibitors DNA Cleavage Etoposide chemistry.chemical_classification Flavonoids biology Topoisomerase Polyphenols DNA Molecular biology Antineoplastic Agents Phytogenic Histone Enzyme DNA Topoisomerases Type II chemistry Biochemistry biology.protein Linear Models Genotoxicity Food Science Biotechnology medicine.drug DNA Damage Half-Life |
| Zdroj: | Molecular nutritionfood research. 55 |
| ISSN: | 1613-4133 |
| Popis: | Scope: DNA damage by genistein and etoposide is determined by the half-life of topoisomerase II–DNA linkage induced [Bandele O. J. and Osheroff N., Biochemistry 2008, 47, 11900]. Here, we test whether this applies generally to dietary flavonoids and therapeutic compounds enhancing topoisomerase II–DNA cleavage (Topo II poisons). Methods and results: We compared the impact of Topo II poisons on DNA residence kinetics of biofluorescent human topoisomerases IIα and IIβ (delineating duration of the DNA-linked enzyme state) with histone 2AX phosphorylation (delineating DNA damage response). Prolongation of topoisomerase II–DNA residence was correlated to DNA damage response, whereas topoisomerase II–DNA linkage was not. Catalytic inhibitors stabilizing topoisomerase II on unbroken DNA also exhibited such a correlation, albeit at a lower level of DNA damage response. Therapeutic Topo II poisons had stronger and more durable effects on enzyme II DNA residence and elicited stronger DNA damage responses than natural or dietary ones. Conclusions: Topoisomerase II-mediated DNA damage appears related to the prolongation of enzyme DNA residence more than to enzyme–DNA cleavage. Due to this reason, genistein and other tested natural and dietary Topo II poisons have a much lower genotoxic potential than therapeutic ones under the conditions of equal topoisomerase II–DNA linkage. |
| Databáze: | OpenAIRE |
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