Interstrand DNA cross-links induced by α,β-unsaturated aldehydes derived from lipid peroxidation and environmental sources

Michael P. Stonez, Young Jin Cho, Hai Huang, Hye Young Kim, Ivan D. Kozekov, Albena Kozekova, Hao Wang, Irina Minko, Robert (Stephen) Lloyd, Thomas M. Harris, Carmelo J. Rizzo

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Abstract

Significant levels of the 1,N2-γ-hydroxypropano-dG adducts of the α,β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxy-2E-nonenal (HNE) have been identified in human DNA, arising from both exogenous and endogenous exposures. They yield interstrand DNA aoss-links between guanines in the neighboring CG and G·C base pairs located in 5′-CpG-3′ sequences, as a result of opening of the 1,N 2-γ-hydroxypropano-dG adducts to form reactive aldehydes that are positioned within the minor groove of duplex DNA. Using a combination of chemical, spectroscopic, and computational methods, we have elucidated the chemistry of cross-link formation in duplex DNA. NMR spectroscopy revealed that, at equilibrium, the acrolein and crotonaldehyde cross-links consist primarily of interstrand carbinolamine linkages between the exocyclic amines of the two guanines located in the neighboring C·G and G·C base pairs located in 5′-CpG-3′ sequences, that maintain the Watson-Crick hydrogen bonding of the cross-linked base pairs. The ability of crotonaldehyde and HNE to form interstrand cross-links depends upon their common relative stereochemistry at the C6 position of the 1,N2-γ-hydroxypropano-dG adduct. The stereochemistry at this center modulates the orientation of the reactive aldehyde within the minor groove of the double-stranded DNA, either facilitating or hindering the cross-linking reactions; it also affects the stabilities of the resulting diastereoisomeric cross-links. 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. Reduced derivatives of these cross-links are useful tools for studying their biological processing. (Chemical Equation Presented)

Original languageEnglish (US)
Pages (from-to)793-804
Number of pages12
JournalAccounts of Chemical Research
Volume41
Issue number7
DOIs
StatePublished - Jul 2008

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2-butenal
Aldehydes
Lipids
DNA
Acrolein
Stereochemistry
Guanine
Transcription
Computational methods
Nuclear magnetic resonance spectroscopy
Amines
Hydrogen bonds
Derivatives
Processing

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Stonez, M. P., Cho, Y. J., Huang, H., Kim, H. Y., Kozekov, I. D., Kozekova, A., ... Rizzo, C. J. (2008). Interstrand DNA cross-links induced by α,β-unsaturated aldehydes derived from lipid peroxidation and environmental sources. Accounts of Chemical Research, 41(7), 793-804. https://doi.org/10.1021/ar700246x

Interstrand DNA cross-links induced by α,β-unsaturated aldehydes derived from lipid peroxidation and environmental sources. / Stonez, Michael P.; Cho, Young Jin; Huang, Hai; Kim, Hye Young; Kozekov, Ivan D.; Kozekova, Albena; Wang, Hao; Minko, Irina; Lloyd, Robert (Stephen); Harris, Thomas M.; Rizzo, Carmelo J.

In: Accounts of Chemical Research, Vol. 41, No. 7, 07.2008, p. 793-804.

Research output: Contribution to journalArticle

Stonez, MP, Cho, YJ, Huang, H, Kim, HY, Kozekov, ID, Kozekova, A, Wang, H, Minko, I, Lloyd, RS, Harris, TM & Rizzo, CJ 2008, 'Interstrand DNA cross-links induced by α,β-unsaturated aldehydes derived from lipid peroxidation and environmental sources', Accounts of Chemical Research, vol. 41, no. 7, pp. 793-804. https://doi.org/10.1021/ar700246x
Stonez, Michael P. ; Cho, Young Jin ; Huang, Hai ; Kim, Hye Young ; Kozekov, Ivan D. ; Kozekova, Albena ; Wang, Hao ; Minko, Irina ; Lloyd, Robert (Stephen) ; Harris, Thomas M. ; Rizzo, Carmelo J. / Interstrand DNA cross-links induced by α,β-unsaturated aldehydes derived from lipid peroxidation and environmental sources. In: Accounts of Chemical Research. 2008 ; Vol. 41, No. 7. pp. 793-804.
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