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Formation of DNA−Protein Cross-Links Between γ-Hydroxypropanodeoxyguanosine and EcoRI
[Image: see text] The toxicity of acrolein, an α,β-unsaturated aldehyde produced during lipid peroxidation, is attributable to its high reactivity toward DNA and cellular proteins. The major acrolein−DNA adduct, γ-hydroxypropano-2′-deoxyguanosine (γ-HOPdG), ring opens to form a reactive N(2)-oxoprop...
Autores principales: | , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651693/ https://www.ncbi.nlm.nih.gov/pubmed/18690724 http://dx.doi.org/10.1021/tx800092g |
Sumario: | [Image: see text] The toxicity of acrolein, an α,β-unsaturated aldehyde produced during lipid peroxidation, is attributable to its high reactivity toward DNA and cellular proteins. The major acrolein−DNA adduct, γ-hydroxypropano-2′-deoxyguanosine (γ-HOPdG), ring opens to form a reactive N(2)-oxopropyl moiety that cross-links to DNA and proteins. We demonstrate the ability of γ-HOPdG in a duplex oligonucleotide to cross-link to a protein (EcoRI) that specifically interacts with DNA at a unique sequence. The formation of a cross-link to EcoRI was dependent on the intimate binding of the enzyme to its γ-HOPdG-modified recognition site. Interestingly, the cross-link did not restrict the ability of EcoRI to cleave DNA substrates. However, stabilization of the cross-link by reduction of the Schiff base linkage resulted in loss of enzyme activity. This work indicates that the γ-HOPdG−EcoRI cross-link is in equilibrium with free oligonucleotide and enzyme. Reversal of cross-link formation allows EcoRI to effect enzymatic cleavage of competitor oligonucleotides. |
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