Send to

Choose Destination
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

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.
Department of Pharmacology, College of Medicine, Inha University, Incheon, Republic of Korea.
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
Section of Electron Microscopy, Section of Brain Structure Information, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.
Forensic DNA Division, Gwangju Institute of National Forensic Service, Jangseong-gun, Jeonnam, Republic of Korea.


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.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center