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Novel mechanism of base excision repair inhibition by low-dose nickel(II): interference of p53-mediated APE1 function
Molecular & Cellular Toxicology ( IF 1.7 ) Pub Date : 2021-03-16 , DOI: 10.1007/s13273-021-00122-z
Hye Lim Kim , Yeo Jin Kim , Nam Gook Kee , Preeyaporn Koedrith , Young Rok Seo

Backgrounds

Nickel is known as a carcinogen through the environmental and occupational exposures. One of carcinogenic mechanisms of nickel is an induction of oxidative stresses and inhibition of DNA repair. But the exact molecular mechanisms by which nickel induces carcinogenicity remains unclear.

Objectives

We selected the sub-lethal dose of nickel in human cells using MTT assay and FACS analysis. To demonstrate the effect of nickel on transcriptional activity of p53, we conducted an electrophoretic mobility shift assay and streptavidin magnetic bead assay. Gadd45a–APE1 complex was confirmed by in situ proximity ligation assay.

Results

We demonstrated that nickel can interfere with the physical interaction between Gadd45a and APE1, in vitro and in situ, as well as APE1 activity in vitro.

Conclusion

Our study implies that the inhibition of p53-mediated APE1 activity in base excision repair might be suggested as one of the potential carcinogenic mechanisms in response to nickel even at a low dose.



中文翻译:

低剂量镍(II)抑制碱基切除修复的新机制:干扰p53介导的APE1功能

背景资料

通过环境和职业接触,镍被称为致癌物。镍的致癌机理之一是氧化应激的诱导和DNA修复的抑制。但是,镍诱导致癌性的确切分子机制仍不清楚。

目标

我们使用MTT分析和FACS分析在人细胞中选择了亚致死剂量的镍。为了证明镍对p53转录活性的影响,我们进行了电泳迁移率迁移测定和链霉亲和素磁珠测定。Gadd45a–APE1复合物通过原位邻近连接测定法确认。

结果

我们证明了镍可以干扰Gadd45a和APE1之间的体外和原位之间的物理相互作用,以及体外APE1的活性。

结论

我们的研究表明,即使在低剂量下,对碱基切除修复中p53介导的APE1活性的抑制也可能被认为是对镍的潜在致癌机制之一。

更新日期:2021-03-16
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