Formation of inter- and intrastrand imine type DNA-DNA cross-links through secondary reactions of aldehydic adducts

Ana M. Sanchez, Ivan D. Kozekov, Thomas M. Harris, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Acrolein-derived DNA adducts of guanine have previously been detected in tissues of several species, including humans, and have been shown to be mutagenic in mammalian cells and potentially carcinogenic in higher organisms. In duplex DNA, the predominant acrolein-derived lesion, γ-hydroxy-1,N 2-propanodeoxyguanosine (γ-HOPdG), exists in an equilibrated mixture of ring-opened and ring-closed forms. We have previously shown that the acyclic form can undergo secondary chemical reactions to form both interstrand DNA-DNA cross-links in a CpG sequence context and DNA-protein and DNA-peptide cross-links. Investigations using duplex DNAs containing γ-HOPdG in a CpG sequence context reversibly created at least two cross-linked species: an imine, which is a minor species but could be readily reduced by NaBH4, and a major heat labile, nonreducible species that we formulate as a carbinolamine cross-link. The DNA came to equilibrium over several days with the carbinolamine species being significantly more abundant than the reducible imine. In an effort to find other types of DNA-DNA cross-links, we have developed a high throughput screen to evaluate the effects of DNA sequence and lesion structure on the formation of reducible interstrand and intrastrand crosslinks. These data reveal that four different lesions, two involving deoxyguanosine and two involving deoxyadenosine, can react with nearby bases to form inter- and intrastrand DNA cross-links.

Original languageEnglish (US)
Pages (from-to)1683-1690
Number of pages8
JournalChemical Research in Toxicology
Volume18
Issue number11
DOIs
StatePublished - Nov 2005

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Imines
DNA
Acrolein
Deoxyguanosine
DNA Adducts
Guanine
DNA sequences
Chemical reactions
Hot Temperature
Cells
Throughput
Tissue
Peptides

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Formation of inter- and intrastrand imine type DNA-DNA cross-links through secondary reactions of aldehydic adducts. / Sanchez, Ana M.; Kozekov, Ivan D.; Harris, Thomas M.; Lloyd, Robert (Stephen).

In: Chemical Research in Toxicology, Vol. 18, No. 11, 11.2005, p. 1683-1690.

Research output: Contribution to journalArticle

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