Premium
Alternariol acts as a topoisomerase poison, preferentially affecting the IIα isoform
Author(s) -
Fehr Markus,
Pahlke Gudrun,
Fritz Jessica,
Christensen Morten O.,
Boege Fritz,
Altemöller Martina,
Podlech Joachim,
Marko Doris
Publication year - 2009
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.200700379
Subject(s) - alternariol , topoisomerase , dna , dna damage , biochemistry , chemistry , dna supercoil , alternaria , biology , microbiology and biotechnology , dna replication , genetics
Alternariol (AOH), a mycotoxin formed by Alternaria alternata , has been reported to possess genotoxic properties. However, the underlying mechanism of action is unclear. Here, we tested the hypothesis that interactions with DNA–topoisomerases play a role in the DNA‐damaging properties of AOH. First we compared DNA‐damaging properties of AOH with other Alternaria mycotoxins such as AOH monomethyl ether (AME), altenuene and isoaltenuene. AOH and AME significantly increased the rate of DNA strand breaks in human carcinoma cells (HT29, A431) at micromolar concentrations, whereas altenuene and isoaltenuene did not affect DNA integrity up to 100 μM. Next, we selected AOH as the most DNA‐damaging Alternaria metabolite for further studies of interactions with DNA topoisomerases. In cell‐free assays, AOH potently inhibited DNA relaxation and stimulated DNA cleavage activities of topoisomerase I, IIα and IIβ. Stabilisation of covalent topoisomerase II–DNA intermediates by AOH was also detectable in cell culture, and here, the IIα isoform was preferentially targeted. AOH is thus characterised as a poison of topoisomerase I and II with a certain selectivity for the IIα isoform. Since topoisomerase poisoning and DNA strand breakage occurred within the same concentration range, poisoning of topoisomerase I and II might at least contribute to the genotoxic properties of AOH.