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- Title
A molecular mechanism of nickel (II): reduction of nucleotide excision repair activity by structural and functional disruption of p53.
- 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
- 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.
- Subjects
NICKEL; NUCLEOTIDE separation; CARCINOGENESIS; CANCER genetics; DNA repair; THERAPEUTICS
- Publication
Carcinogenesis, 2018, Vol 39, Issue 9, p1157
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgy070