Journal Article

The major lipid peroxidation product, <i>trans-</i>4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human <i>p53</i> gene, a unique mutational hotspot in hepatocellular carcinoma

Wenwei Hu, Zhaohui Feng, Jamie Eveleigh, Ganesh Iyer, Jishen Pan, Shantu Amin, Fung-Lung Chung and Moon-shong Tang

in Carcinogenesis

Volume 23, issue 11, pages 1781-1789
Published in print November 2002 | ISSN: 0143-3334
Published online November 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.11.1781
The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma

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Trans-4-hydroxy-2-nonenal (4-HNE), a major electrophilic by-product of lipid peroxidation, is able to interact with DNA to form exocyclic guanine adducts. 4-HNE is a mutagen and a significant amount of 4-HNE–guanine adduct has been detected in normal cells. Recently, it has been reported that exposure of the wild-type p53 human lymphoblastoid cell line to 4-HNE causes a high frequency of G to T transversion mutations at the third base of codon 249 (-AGG*-) in the p53 gene, a mutational hotspot in human cancers, particularly hepatocellular carcinoma. These findings raise a possibility that 4-HNE could be an important etiological agent for human cancers that have a mutation at codon 249 of the p53 gene. However, to date, the sequence specificity of 4-HNE–DNA binding remains unclear due to the lack of methodology. To address this question, we have developed a method, using UvrABC nuclease, a nucleotide excision repair enzyme complex isolated from Escherichia coli, to map the distribution of 4-HNE–DNA adducts in human p53 gene at the nucleotide sequence level. We found that 4-HNE–DNA adducts are preferentially formed at the third base of codon 249 in the p53 gene. The preferential binding of 4-HNE was also observed at codon 174, which has the same sequence and the same nearest neighbor sequences (-GAGG*C-) as codon 249. These results suggest that 4-HNE may be an important etiological agent for human cancers that have a mutation at codon 249 of the p53 gene.

Keywords: AFB1, aflatoxin B1; AFB1-DE, aflatoxin B1 8,9-diol epoxide; APRT, adenine phosphoribosyltransferase; BCDE, benzo[g]chrysene diol epoxide; BPDE, benzo[a]pyrene diol epoxide; CCC, covalently closed circle; 4-HNE, trans-4-hydroxy-2-nonenal; 4-HNE-dG, 6-(1-hydroxyhexanyl)-8-hydroxy 1,N2-propano-2′-deoxyguansine; NAAAF, N-acetoxy-2-acetylaminofluorene; OC, open circle; PAH, polycyclic aromatic hydrocarbon; SAM, S-adenosylmethionine

Journal Article.  6834 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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