DNA damage and repair kinetics of the Alternaria mycotoxins alternariol, altertoxin II and stemphyltoxin III in cultured cells
DNA damage and repair kinetics of the Alternaria mycotoxins alternariol, altertoxin II and stemphyltoxin III in cultured cells
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DOI：
10.1016/j.mrgentox.2016.02.001
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发表时间：
2016-03-01
影响因子：
1.9
通讯作者：
Koeberle, Beate
中科院分区：
文献类型：
--
作者：
Fleck, Stefanie C.;Sauter, Friederike;Koeberle, Beate
链格孢霉菌毒素链格孢醇 (AOH) 和链格孢毒素 It (ATX II) 先前已被证明可在细菌和哺乳动物细胞中引起诱变和基因毒性作用，尽管其活性截然不同。例如，ATX II 的致突变性比 AOH 高约 50 倍。我们现在报告茎菲毒素 III (STTX III) 也具有高度诱变性。与二苯并-α-吡喃酮 AOH 相比，较低浓度的苝醌 ATX II 和 STTX III 的作用更显着，表明遗传毒性潜力对化学结构的显着依赖性，并且进一步表明潜在的作用模式可能不同。我们现在进一步研究了AOH、ATX II和STTX III诱导的DNA损伤类型，以及修复动力学及其对核苷酸切除修复（NER）状态的依赖性。AOH因拓扑异构酶IIα中毒而诱导的DNA双链断裂在不到2小时内被完全修复。在无细胞条件下，也可以在低浓度下测量 ATX II 和 STTX III 对拓扑异构酶 II α 的抑制，但苝醌是催化抑制剂而不是拓扑异构酶毒物，并且不会诱导 DSB。 ATX II 和 STTX III 引起的 DNA 链断裂更加持久，并且在 24 小时内无法完全修复。修复率对 NER 状态的依赖性只能在 STTX III 中得到证实，从而导致 NER 缺陷细胞中 DNA 损伤的积累。结合发现 DNA 糖基化酶甲酰胺嘧啶-DNA 糖基化酶 (Fpg)，而不是 T4 核酸内切酶 V，能够产生可通过碱性解旋测定测量的额外 DNA 链断裂，我们得出结论，具有环氧基团的苝醌的遗传毒性可能是由 DNA 加合物的形成引起的，该加合物可能会转化为 Fpg 敏感位点。 (C) 2016 Elsevier B.V. 保留所有权利。
The Altemaria mycotoxins alternariol (AOH) and altertoxin It (ATX II) have previously been shown to elicit mutagenic and genotoxic effects in bacterial and mammalian cells, although with vastly different activities. For example, ATX II was about 50 times more mutagenic than AOH. We now report that stemphyltoxin III (STTX III) is also highly mutagenic. The more pronounced effects of the perylene quinones ATX II and STTX III at lower concentrations compared to the dibenzo-alpha-pyrone AOH indicate a marked dependence of the genotoxic potential on the chemical structure and furthermore suggest that the underlying modes of action maybe different. We have now further investigated the type of DNA damage induced by AOH, ATX II and STTX III, as well as the repair kinetics and their dependence on the status of nucleotide excision repair (NER).DNA double strand breaks induced by AOH due to poisoning of topoisomerase II alpha were completely repaired in less than 2 h. Under cell-free conditions, inhibition of topoisomerase II alpha could also be measured for ATX II and STTX III at low concentrations, but the perylene quinones were catalytic inhibitors rather than topoisomerase poisons and did not induce DSBs. DNA strand breaks induced by ATX II and STTX III were more persistent and not completely repaired within 24h. A dependence of the repair rate on the NER status could only be demonstrated for STTX III, resulting in an accumulation of DNA damage in NER-deficient cells. Together with the finding that the DNA glycosylase formamidopyrimidine-DNA glycosylase (Fpg), but not T4 endonuclease V, is able to generate additional DNA strand breaks measurable by the alkaline unwinding assay, we conclude that the genotoxicity of the perylene quinones with an epoxide group is probably caused by the formation of DNA adducts which may be converted to Fpg sensitive sites. (C) 2016 Elsevier B.V. All rights reserved.