Studies on mechanisms underlying genotoxic thresholds through genetic modification of DNA polymerase zeta

在调节毒理学中，一个公理是，遗传毒性化学物质的作用没有门槛。因此，即使在非常低的浓度下，遗传毒性物质也不允许存在于食品添加剂和其他物质中。然而，人类拥有多种自卫机制，这些机制可能会在低剂量下抑制化学物质的遗传毒性。可以预期，自卫机制可能构成遗传毒性的实用阈值。在这项研究中，我们检查了DNA聚合酶Zeta是否参与跨病变DNA合成在实际阈值中发挥作用的可能性。为此，我们设计了表达转基因DNA聚合酶Zeta的人类细胞。表达低活性DNA聚合酶Zeta变异体的细胞对氧化遗传毒性物质的敏感性比野生型细胞高得多。我们得出结论，DNA聚合酶Zeta是实际遗传毒性阈值的重要组成部分。

In regulatory toxicology, it is an axiom that there is no threshold for the action of genotoxic chemicals. Thus, genotoxic agents are not allowed to be present in food additives and others even at very low concentrations. However, humans possess various self defense mechanisms, which may suppress genotoxicity of chemicals at low doses. It is expected that self-defense mechanisms may constitute practical threshold for genotoxicity. In this study, we examined the possibility whether DNA polymerase zeta involved in translesion DNA synthesis plays a role in the practical threshold. To this end, we engineered human cells that expressed genetically modified DNA polymerase zeta. The cells expressing a variant of DNA polymerase zeta with low activity exhibited much higher sensitivity to oxidative genotoxic agents than the wild-type cells. We concluded that DNA polymerase zeta is an important constituent of the practical threshold for genotoxicity.