Inhibition of Poly(ADP-ribose) Polymerase-1 by Arsenite Interferes with Repair of Oxidative DNA Damage
Inhibition of Poly(ADP-ribose) Polymerase-1 by Arsenite Interferes with Repair of Oxidative DNA Damage
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DOI：
10.1074/jbc.m805566200
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发表时间：
2009-03-13
影响因子：
4.8
通讯作者：
Liu, Ke Jian
中科院分区：
文献类型：
--
作者：
Ding, Wei;Liu, Wenlan;Liu, Ke Jian
当砷与其他致癌物（包括紫外线辐射（UVR））结合时，会促进皮肤肿瘤的形成。在这项研究中，我们报告说，低微摩尔浓度的亚砷酸盐可协同增加 UVR 诱导的人类角质形成细胞中的氧化 DNA 损伤，如通过 8-羟基-2'-脱氧鸟嘌呤 (8-OHdG) 形成检测到的。聚（ADP-核糖）聚合酶-1 (PARP-1) 参与碱基切除修复，这是修复 8-OHdG 损伤的过程。亚砷酸盐以浓度依赖性方式抑制 UVR 诱导的 PARP-1 激活。 3-氨基苯甲酰胺抑制 PARP-1 活性或沉默 PARP-1 表达的小干扰 RNA 显着增加 UVR 诱导的 8-OHdG 形成，表明亚砷酸盐抑制 PARP-1 活性有助于氧化 DNA 损伤。 PARP-1 是一种锌指蛋白，质谱分析表明亚砷酸盐可以占据代表 PARP-1 第一个锌指 (PARPzf) 的合成脱肽。当 PARPzf 肽与 Zn(II) 预孵育，然后与浓度不断增加的亚砷酸盐一起孵育时，ZnPARPzf 信号会降低，而 AsPARPzf 信号强度会随着亚砷酸盐剂量的变化而增加，这表明锌和亚砷酸盐之间存在对同一结合位点的竞争。添加 Zn(II) 可消除亚砷酸盐对 UVR 刺激的 8-OHdG 生成的增强作用，并恢复 PARP-1 活性。我们的研究结果表明亚砷酸盐抑制氧化性 DNA 损伤修复，并表明亚砷酸盐与 PARP-1 锌指结构域的相互作用有助于亚砷酸盐抑制 PARP-1 活性。亚砷酸盐对聚（ADP-核糖基）化的抑制是已报道的砷在 UVR 诱导的皮肤癌中的协同致癌活性的一种可能机制。
Arsenic enhances skin tumor formation when combined with other carcinogens, including UV radiation (UVR). In this study we report that low micromolar concentrations of arsenite synergistically increases UVR-induced oxidative DNA damage in human keratinocytes as detected by 8-hydroxyl-2'-deoxyguanine (8-OHdG) formation. Poly(ADP-ribose) polymerase-1 (PARP-1) is involved in base excision repair, a process that repairs 8-OHdG lesions. Arsenite suppresses UVR-induced PARP-1 activation in a concentration-dependent manner. Inhibition of PARP-1 activity by 3-aminobenzamide or small interfering RNA silencing of PARP-1 expression significantly increases UVR-induced 8-OHdG formation, suggesting that inhibition of PARP-1 activity by arsenite contributes to oxidative DNA damage. PARP-1 is a zinc finger protein, and mass spectrometry analysis reveals that arsenite can occupy a synthetic apopeptide representing the first zinc finger of PARP-1 (PARPzf). When the PARPzf peptide is preincubated with Zn(II) followed by incubation with increasing concentrations of arsenite, the ZnPARPzf signal is decreased while the AsPARPzf signal intensity is increased as a function of arsenite dose, suggesting a competition between zinc and arsenite for the same binding site. Addition of Zn(II) abolished arsenite enhancement of UVR-stimulated 8-OHdG generation and restored PARP-1 activity. Our findings demonstrate that arsenite inhibits oxidative DNA damage repair and suggest that interaction of arsenite with the PARP-1 zinc finger domain contributes to the inhibition of PARP-1 activity by arsenite. Arsenite inhibition of poly( ADP-ribosyl)ation is one likely mechanism for the reported co-carcinogenic activities of arsenic in UVR-induced skin carcinogenesis.