Low concentrations of antimony impair DNA damage signaling and the repair of radiation-induced DSB in HeLa S3 cells
Low concentrations of antimony impair DNA damage signaling and the repair of radiation-induced DSB in HeLa S3 cells
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DOI：
10.1007/s00204-017-2004-z
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发表时间：
2017-12-01
影响因子：
6.1
通讯作者：
Hartwig, Andrea
中科院分区：
文献类型：
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作者：
Koch, Barbara;Maser, Elena;Hartwig, Andrea
锑被用于各种工业应用，导致大量的环境和职业暴露。IARC和MAK委员会主要基于动物实验，将锑及其无机化合物分别归类为2B类或2类致癌物质。然而，潜在的行动模式(S)在很大程度上仍是未知的。在本研究中，我们研究了非细胞毒性浓度的SbCl3对HeLa S3细胞DNA DSB修复和细胞周期控制的影响。我们用伽马射线诱导了DSB，并分析了Sb对DSB修复机制潜在分子靶点的抑制作用。Sb干扰细胞周期控制，影响Chk1的磷酸化。此外，通过脉冲场凝胶电泳法和G1期和G2期细胞的伽马H_2AX焦点形成监测，Sb的存在使DSB的修复受到损害。具体而言，BRCA1和RAD51被确定为分子靶标。我们的结果表明，非同源末端连接(NHEJ)和同源重组(HR)都受到干扰，抑制作用可能是通过与关键半胱氨酸基的相互作用来解释的；这需要进一步研究。总之，这些结果为DNA修复过程的损伤提供了进一步的证据，这是锑诱导致癌的一个潜在机制。
Antimony is utilized in a large variety of industrial applications, leading to significant environmental and occupational exposure. Mainly based on animal experiments, the IARC and MAK Commission have classified antimony and its inorganic compounds as Group 2B or 2 carcinogens, respectively. However, the underlying mode(s) of action are still largely unknown. In the present study, we investigated the impact of non-cytotoxic up to cytotoxic concentrations of SbCl3 on DNA DSB repair and cell cycle control in HeLa S3 cells. We induced DSB by gamma-irradiation and analyzed inhibitory actions of antimony on potential molecular targets of the DSB repair machinery. Antimony disturbed cell cycle control, affecting phosphorylation of Chk1. Furthermore, the repair of DSB was impaired in the presence of antimony, as monitored by pulsed-field gel electrophoresis and gamma H2AX foci formation of cells in G1 and G2 phase. Specifically, BRCA1 and RAD51 were identified as molecular targets. Our results point towards an interference with both non-homologous end-joining (NHEJ) and homologous recombination (HR), and inhibitory effects may be explained by interactions with critical cysteine groups; this needs to be further investigated. Altogether, the results provide further evidence for the impairment of DNA repair processes as one underlying mechanism in antimony-induced carcinogenicity.