Department of Life Science, Institute of Environmental Medicine, Dongguk University Biomedi Campus, Goyang-si, Gyeonggi-do, Republic of Korea.
Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
Carcinogenesis. 2018 Sep 21;39(9):1157-1164. doi: 10.1093/carcin/bgy070.
Nickel is a major carcinogen that is implicated in tumor development through occupational and environmental exposure. Although the exact molecular mechanisms of carcinogenesis by low-level nickel remain unclear, inhibition of DNA repair is frequently considered to be a critical mechanism of carcinogenesis. Here, we investigated whether low concentrations of nickel would affect p53-mediated DNA repair, especially nucleotide excision repair. Our results showed that nickel inhibited the promoter binding activity of p53 on the downstream gene GADD45A, as a result of the disturbance of p53 oligomerization by nickel. In addition, we demonstrated that nickel exposure trigger the reduction of GADD45A-mediated DNA repair by impairing the physical interactions between GADD45A and proliferating cell nuclear antigen or xeroderma pigmentosum G. Notably, in the GADD45A-knockdown system, the levels of unrepaired DNA photoproducts were higher than wild-type cells, elucidating the importance of GADD45A in the nickel-associated inhibition of DNA repair. These results imply that inhibition of p53-mediated DNA repair can be considered a potential carcinogenic mechanism of nickel at low concentrations.
镍是一种主要的致癌物质，通过职业和环境暴露与肿瘤的发展有关。虽然低水平镍致癌的确切分子机制尚不清楚，但抑制 DNA 修复通常被认为是致癌作用的关键机制。在这里，我们研究了低浓度的镍是否会影响 p53 介导的 DNA 修复，特别是核苷酸切除修复。我们的结果表明，镍通过干扰 p53 寡聚化来抑制 p53 对下游基因 GADD45A 的启动子结合活性。此外，我们证明镍暴露通过损害 GADD45A 与增殖细胞核抗原或着色性干皮病 G 之间的物理相互作用，触发 GADD45A 介导的 DNA 修复减少。值得注意的是，在 GADD45A 敲低系统中，未修复的 DNA 光产物水平高于野生型细胞，这阐明了 GADD45A 在镍相关的 DNA 修复抑制中的重要性。这些结果表明，抑制 p53 介导的 DNA 修复可以被认为是低浓度镍的一种潜在致癌机制。
