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Carcinogenesis. 2018 Sep 21;39(9):1157-1164. doi: 10.1093/carcin/bgy070.

A molecular mechanism of nickel (II): reduction of nucleotide excision repair activity by structural and functional disruption of p53.

Author information

1
Department of Life Science, Institute of Environmental Medicine, Dongguk University Biomedi Campus, Goyang-si, Gyeonggi-do, Republic of Korea.
2
Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
3
Department of Pharmacology, College of Medicine, Inha University, Incheon, Republic of Korea.
4
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
5
Section of Electron Microscopy, Section of Brain Structure Information, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.
6
Forensic DNA Division, Gwangju Institute of National Forensic Service, Jangseong-gun, Jeonnam, Republic of Korea.

Abstract

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.

PMID:
29931256
DOI:
10.1093/carcin/bgy070
[Indexed for MEDLINE]

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