Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium.
Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium.
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DOI：
10.1016/j.taap.2015.11.017
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发表时间：
2016-01-15
影响因子：
3.8
通讯作者：
Hudson LG
中科院分区：
文献类型：
--
作者：
Cooper KL;Dashner EJ;Tsosie R;Cho YM;Lewis J;Hudson LG
铀在生物系统内具有放射性和非放射性效应，并且越来越多的证据表明铀通过其重金属特性具有遗传毒性和致癌特性。在这项研究中，我们报告低浓度的铀（醋酸双氧铀；<10 μM）对人胚胎肾细胞或正常人角质形成细胞没有细胞毒性；然而，铀会加剧过氧化氢引起的 DNA 损伤和细胞毒性，这表明铀可能会抑制 DNA 修复过程。低微摩尔浓度的乙酸双氧铀会抑制锌指 DNA 修复蛋白聚（ADP-核糖）聚合酶（PARP）-1，并导致 PARP-1 蛋白中的锌损失。乙酸铀酰暴露还会导致锌指 DNA 修复蛋白色素干皮病、补体 A 组 (XPA) 和 aprataxin (APTX) 中的锌损失。与观察到的 DNA 修复蛋白锌指功能的抑制一致，暴露于乙酸双氧铀增强了诱导的 DNA 损伤的保留。乙酸双氧铀与锌共孵育很大程度上克服了铀对 PARP-1 活性和 DNA 损伤的影响。这些发现证明，低浓度的铀可以通过破坏特定目标 DNA 修复蛋白的锌指结构域来抑制 DNA 修复。这可能为解释已发表的观察结果提供了机制基础，即铀暴露与暴露人群中 DNA 修复缺陷有关。
Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; <10 μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations.