Dual actions involved in arsenite-induced oxidative DNA damage.
Dual actions involved in arsenite-induced oxidative DNA damage.
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DOI：
10.1021/tx8001548
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发表时间：
2008-09
影响因子：
4.1
通讯作者：
Liu, Ke Han
中科院分区：
文献类型：
--
作者：
Qin, Xu-Jun;Hudson, Laurie G.;Liu, Wenlan;Ding, Wei;Cooper, Karen L.;Liu, Ke Han
砷是公认的人类致癌物，但其致癌机制尚不清楚。氧化应激和DNA损伤修复的抑制被认为是砷的潜在致癌作用。本研究验证了亚砷酸盐不仅可以诱导氧化应激，还可以抑制DNA碱基切除修复蛋白聚（adp -核糖）聚合酶-1 （PARP-1）的活性，导致砷诱导的DNA氧化损伤加重。用亚砷酸盐处理HaCat细胞24小时后，测定8-羟基-2 ' -脱氧鸟苷（8-OHdG）、PARP-1活性和活性氧（ROS）。补充锌和PARP-1 siRNA分别增加或降低PARP-1蛋白的生理功能。高浓度（10μM或更高）时，亚砷酸盐显著诱导DNA氧化损伤，并形成8-OHdG。在较低浓度（1μM）下，亚砷酸盐不能产生可检测到的8-OHdG，但仍能有效抑制PARP-1的活性。补锌减少了8-OHdG的形成，恢复了被亚砷酸盐抑制的PARP-1活性，但没有减少ROS的产生。SiRNA敲低PARP-1对砷诱导的8-OHdG水平无影响，而过氧化氢诱导的8-OHdG水平显著升高，提示PARP-1是亚砷酸盐的分子靶点。我们的研究结果表明，除了在较高浓度下诱导氧化应激外，即使在非常低的浓度下，亚砷酸盐也可以抑制关键DNA修复蛋白PARP-1的功能，从而加剧亚砷酸盐以及其他氧化剂产生的整体氧化DNA损伤。
Arsenic is a recognized human carcinogen, but the mechanism of carcinogenesis is not well understood. Oxidative stress and inhibition of DNA damage repair have been postulated as potential carcinogenic actions of arsenic. The present study tests the hypothesis that arsenite not only induces oxidative stress, but also inhibits the activity of the DNA base excision repair protein, poly(ADP-ribose) polymerase-1 (PARP-1), leading to exacerbation of the oxidative DNA damage induced by arsenic. HaCat cells were treated with arsenite for 24 hrs before measuring 8-hydroxyl-2′-deoxyguanosine (8-OHdG), PARP-1 activity, and reactive oxygen species (ROS). Zinc supplementation and PARP-1 siRNA were used to increase or decrease, respectively, the PARP-1 protein’s physiological function. At high concentrations (10μM or higher), arsenite greatly induced oxidative DNA damage, as indicated by 8-OHdG formation. At lower concentrations (1μM), arsenite did not produce detectable 8-OHdG, but was still able to effectively inhibit PARP-1 activity. Zinc supplementation reduced the formation of 8-OHdG, restored the PARP-1 activity inhibited by arsenite, but did not decrease ROS production. SiRNA knockdown of PARP-1 did not affect the 8-OHdG level induced by arsenic, while it greatly increased the 8-OHdG level produced by hydrogen peroxide indicating that PARP-1 is a molecular target of arsenite. Our findings demonstrate that in addition to inducing oxidative stress at higher concentrations, arsenite can also inhibit the function of a key DNA repair protein, PARP-1, even at very low concentrations, thus exacerbating the overall oxidative DNA damage produced by arsenite, and potentially, by other oxidants as well.
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影响因子：
10.4
作者：
Applebaum KM;Karagas MR;Hunter DJ;Catalano PJ;Byler SH;Morris S;Nelson HH
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影响因子：
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影响因子：
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作者：
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