Mutational spectrum and genotoxicity of the major lipid peroxidation product, trans-4-hydroxy-2-nonenal, induced DNA adducts in nucleotide excision repair-proficient and -deficient human cell

Zhaohui Feng, Wenwei Hu, Shantu Amin, Moon shong Tang

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

trans-4-Hydroxy-2-nonenal (4-HNE), a major product of lipid peroxidation, is able to interact with DNA to form 6-(1-hydroxyhexanyl)-8-hydroxy-1,N2-propano-2′ -deoxyguanosine (4-HNE-dG) 1 adducts, but its genotoxicity and mutagenicity remain elusive. It has been reported that 4-HNE treatment zn in human cells induces a high frequency of G·C to T·A mutations at the third base of codon 249 (AGG*) of the p53 gene, a mutational hot spot in human cancers, particularly in hepatocellular carcinoma. This G·C to T·A transversion at codon 249, however, has been thought to be caused by etheno-DNA adducts induced by the endogenous metabolite of 4-HNE, 2,3-epoxy-4-hydroxynonanal. We have recently found that 4-HNE preferentially forms 4-HNE-dG adducts at the GAGGz.ast;C/A sequence in the p53 gene including codon 249 (GAGG*C). Our finding supports the possibility that G·C to T.A mutations at codon 249 may be induced by 4-HNE-dG adducts. To investigate this possibility, we determined the mutational spectrum induced by 4-HNE-dG adducts in the supF gene of shuttle vector pSP189 replicated in human cells. We have found that 4-HNE-dG adducts are mutagenic and genotoxic in human cells, and that G·C to T·A transversions are the most prevalent mutations induced by 4-HNE-dG adducts. Furthermore, 4-HNE-dG adducts induce a significantly higher level of genotoxicity and mutagenicity in nucleotide excision repair (NER)-deficient human and Escherichia coli cells than in NER-proficient cells, indicating that NER is a major pathway for repairing 4-HNE-dG adducts in both human and E. coli cells. Together, these results suggest that 4-HNE-dG adducts may contribute greatly to the G·C to T·A mutation at codon 249 of the p53 gene, and may play an important role in carcinogenesis.

Original languageEnglish (US)
Pages (from-to)7848-7854
Number of pages7
JournalBiochemistry
Volume42
Issue number25
DOIs
StatePublished - Jul 1 2003

All Science Journal Classification (ASJC) codes

  • Biochemistry

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