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

• Published in: Carcinogenesis (New York) Vol. 39; no. 9; pp. 1157 - 1164
• Main Authors: Kim, Yeo Jin, Lee, Young Ju, Kim, Hyo Jeong, Kim, Hyun Soo, Kang, Mi-Sun, Lee, Sung-Keun, Park, Moo Kyun, Murata, Kazuyoshi, Kim, Hye Lim, Seo, Young Rok
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 21.09.2018
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgy070

This study demonstrates the potential carcinogenic mechanism of low-dose nickel, especially p53-mediated nucleotide excision repair. The functional defect of p53 by nickel influences the expression of DNA repair key contributor, GADD45A, as well as the physical interactions between major nucleotide excision repair factors. 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.