DNA cross-link induced by trans-4-hydroxynonenal

Hai Huang, Ivan D. Kozekov, Albena Kozekova, Hao Wang, Robert (Stephen) Lloyd, Carmelo J. Rizzo, Michael P. Stone

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Trans-4-Hydroxynonenal (HNE) is a peroxidation product of ω-6 polyunsaturated fatty acids. Michael addition of HNE to deoxyguanosine yields four diastereomeric 1,N2-dG adducts. The adduct of (6S,8R,11S) stereochemistry forms interstrand N2-dG:N2-dG cross-links in the 5′-CpG-3′ sequence. It has been compared with the (6R,8S,11R) adduct, incorporated into 5′-d(GCTAGCXAGTCC)-3′·5′- d(GGACTCGCTAGC)-3′, containing the 5′-CpG-3′ sequence (X = HNE-dG). Both adducts rearrange in DNA to N2-dG aldehydes. These aldehydes exist in equilibrium with diastereomeric cyclic hemiacetals, in which the latter predominate at equilibrium. These cyclic hemiacetals mask the aldehydes, explaining why DNA cross-linking is slow compared to related 1,N 2-dG adducts formed by acrolein and crotonaldehyde. Both the (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals are located within the minor groove. However, the (6S,8R,11S) cyclic hemiacetal orients in the 5′-direction, while the (6R,8S,11R) cyclic hemiacetal orients in the 3′-direction. The conformations of the diastereomeric N2-dG aldehydes, which are the reactive species involved in DNA cross-link formation, have been calculated using molecular mechanics methods. The (6S,11S) aldehyde orients in the 5′-direction, while the (6R,11R) aldehyde orients in the 3′-direction. This suggests a kinetic basis to explain, in part, why the (6S,8R,11S) HNE adduct forms interchain cross-links in the 5′-CpG-3′ sequence, whereas (6R,8S,11R) HNE adduct does not. The presence of these cross-links in vivo is anticipated to interfere with DNA replication and transcription, thereby contributing to the etiology of human disease.

Original languageEnglish (US)
Pages (from-to)625-634
Number of pages10
JournalEnvironmental and Molecular Mutagenesis
Volume51
Issue number6
DOIs
StatePublished - Jul 2010

Fingerprint

Aldehydes
DNA
2-butenal
Acrolein
Deoxyguanosine
Masks
Mechanics
DNA Replication
Unsaturated Fatty Acids
4-hydroxy-2-nonenal
Direction compound

Keywords

  • DNA cross-links
  • DNA damage
  • Hydroxynonenal

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Epidemiology
  • Genetics(clinical)

Cite this

Huang, H., Kozekov, I. D., Kozekova, A., Wang, H., Lloyd, R. S., Rizzo, C. J., & Stone, M. P. (2010). DNA cross-link induced by trans-4-hydroxynonenal. Environmental and Molecular Mutagenesis, 51(6), 625-634. https://doi.org/10.1002/em.20599

DNA cross-link induced by trans-4-hydroxynonenal. / Huang, Hai; Kozekov, Ivan D.; Kozekova, Albena; Wang, Hao; Lloyd, Robert (Stephen); Rizzo, Carmelo J.; Stone, Michael P.

In: Environmental and Molecular Mutagenesis, Vol. 51, No. 6, 07.2010, p. 625-634.

Research output: Contribution to journalArticle

Huang, H, Kozekov, ID, Kozekova, A, Wang, H, Lloyd, RS, Rizzo, CJ & Stone, MP 2010, 'DNA cross-link induced by trans-4-hydroxynonenal', Environmental and Molecular Mutagenesis, vol. 51, no. 6, pp. 625-634. https://doi.org/10.1002/em.20599
Huang, Hai ; Kozekov, Ivan D. ; Kozekova, Albena ; Wang, Hao ; Lloyd, Robert (Stephen) ; Rizzo, Carmelo J. ; Stone, Michael P. / DNA cross-link induced by trans-4-hydroxynonenal. In: Environmental and Molecular Mutagenesis. 2010 ; Vol. 51, No. 6. pp. 625-634.
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