Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5′-CpG-3′ sequence by the acrolein-derived γ-OH-1,N2-propano-2′-deoxyguanosine DNA adduct

Young Jin Cho, Hye Young Kim, Hai Huang, Alvira Slutsky, Irina Minko, Hao Wang, Lubomir V. Nechev, Ivan D. Kozekov, Albena Kozekova, Pamela Tamura, Jaison Jacob, Markus Voehler, Thomas M. Harris, Robert (Stephen) Lloyd, Carmelo J. Rizzo, Michael P. Stone

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Abstract

The interstrand N2,N2-dG DNA cross-linking chemistry of the acrolein-derived γ-OH-1,N2-propanodeoxyguanosine (γ-OH-PdG) adduct in the 5′-CpG-3′ sequence was monitored within a dodecamer duplex by NMR spectroscopy, in situ, using a series of site-specific 13C- and 15N-edited experiments. At equilibrium 40% of the DNA was cross-linked, with the carbinolamine form of the cross-link predominating. The cross-link existed in equilibrium with the non-crosslinked N2-(3-oxo-propyl)-dG aldehyde and its geminal diol hydrate. The ratio of aldehyde/diol increased at higher temperatures. The 1,N2-dG cyclic adduct was not detected. Molecular modeling suggested that the carbinolamine linkage should be capable of maintaining Watson-Crick hydrogen bonding at both of the tandem C-G base pairs. In contrast, dehydration of the carbinolamine cross-link to an imine (Schiff base) cross-link, or cyclization of the latter to form a pyrimidopurinone cross-link, was predicted to require disruption of Watson-Crick hydrogen bonding at one or both of the tandem cross-linked C-G base pairs. When the γ-OH-PdG adduct contained within the 5′-CpG-3′ sequence was instead annealed into duplex DNA opposite T, a mixture of the 1,N2-dG cyclic adduct, the aldehyde, and the diol, but no cross-link, was observed. With this mismatched duplex, reaction with the tetrapeptide KWKK formed DNA-peptide cross-links efficiently. When annealed opposite dA, γ-OH-PdG remained as the 1,N2-dG cyclic adduct although transient epimerization was detected by trapping with the peptide KWKK. The results provide a rationale for the stability of interstrand cross-links formed by acrolein and perhaps other αβ-unsaturated aldehydes. These sequence-specific carbinolamine cross-links are anticipated to interfere with DNA replication and contribute to acrolein-mediated genotoxicity.

Original languageEnglish (US)
Pages (from-to)17686-17696
Number of pages11
JournalJournal of the American Chemical Society
Volume127
Issue number50
DOIs
StatePublished - Dec 21 2005

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Acrolein
DNA Adducts
Aldehydes
DNA
Hydrogen Bonding
Base Pairing
Peptides
Hydrogen bonds
Imines
Schiff Bases
Cyclization
DNA Replication
Dehydration
Molecular modeling
Hydrates
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance spectroscopy
Temperature
hydroxide ion
1,N2-propano-2'-deoxyguanosine

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5′-CpG-3′ sequence by the acrolein-derived γ-OH-1,N2-propano-2′-deoxyguanosine DNA adduct. / Cho, Young Jin; Kim, Hye Young; Huang, Hai; Slutsky, Alvira; Minko, Irina; Wang, Hao; Nechev, Lubomir V.; Kozekov, Ivan D.; Kozekova, Albena; Tamura, Pamela; Jacob, Jaison; Voehler, Markus; Harris, Thomas M.; Lloyd, Robert (Stephen); Rizzo, Carmelo J.; Stone, Michael P.

In: Journal of the American Chemical Society, Vol. 127, No. 50, 21.12.2005, p. 17686-17696.

Research output: Contribution to journalArticle

Cho, YJ, Kim, HY, Huang, H, Slutsky, A, Minko, I, Wang, H, Nechev, LV, Kozekov, ID, Kozekova, A, Tamura, P, Jacob, J, Voehler, M, Harris, TM, Lloyd, RS, Rizzo, CJ & Stone, MP 2005, 'Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5′-CpG-3′ sequence by the acrolein-derived γ-OH-1,N2-propano-2′-deoxyguanosine DNA adduct', Journal of the American Chemical Society, vol. 127, no. 50, pp. 17686-17696. https://doi.org/10.1021/ja053897e
Cho, Young Jin ; Kim, Hye Young ; Huang, Hai ; Slutsky, Alvira ; Minko, Irina ; Wang, Hao ; Nechev, Lubomir V. ; Kozekov, Ivan D. ; Kozekova, Albena ; Tamura, Pamela ; Jacob, Jaison ; Voehler, Markus ; Harris, Thomas M. ; Lloyd, Robert (Stephen) ; Rizzo, Carmelo J. ; Stone, Michael P. / Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5′-CpG-3′ sequence by the acrolein-derived γ-OH-1,N2-propano-2′-deoxyguanosine DNA adduct. In: Journal of the American Chemical Society. 2005 ; Vol. 127, No. 50. pp. 17686-17696.
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title = "Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5′-CpG-3′ sequence by the acrolein-derived γ-OH-1,N2-propano-2′-deoxyguanosine DNA adduct",
abstract = "The interstrand N2,N2-dG DNA cross-linking chemistry of the acrolein-derived γ-OH-1,N2-propanodeoxyguanosine (γ-OH-PdG) adduct in the 5′-CpG-3′ sequence was monitored within a dodecamer duplex by NMR spectroscopy, in situ, using a series of site-specific 13C- and 15N-edited experiments. At equilibrium 40{\%} of the DNA was cross-linked, with the carbinolamine form of the cross-link predominating. The cross-link existed in equilibrium with the non-crosslinked N2-(3-oxo-propyl)-dG aldehyde and its geminal diol hydrate. The ratio of aldehyde/diol increased at higher temperatures. The 1,N2-dG cyclic adduct was not detected. Molecular modeling suggested that the carbinolamine linkage should be capable of maintaining Watson-Crick hydrogen bonding at both of the tandem C-G base pairs. In contrast, dehydration of the carbinolamine cross-link to an imine (Schiff base) cross-link, or cyclization of the latter to form a pyrimidopurinone cross-link, was predicted to require disruption of Watson-Crick hydrogen bonding at one or both of the tandem cross-linked C-G base pairs. When the γ-OH-PdG adduct contained within the 5′-CpG-3′ sequence was instead annealed into duplex DNA opposite T, a mixture of the 1,N2-dG cyclic adduct, the aldehyde, and the diol, but no cross-link, was observed. With this mismatched duplex, reaction with the tetrapeptide KWKK formed DNA-peptide cross-links efficiently. When annealed opposite dA, γ-OH-PdG remained as the 1,N2-dG cyclic adduct although transient epimerization was detected by trapping with the peptide KWKK. The results provide a rationale for the stability of interstrand cross-links formed by acrolein and perhaps other αβ-unsaturated aldehydes. These sequence-specific carbinolamine cross-links are anticipated to interfere with DNA replication and contribute to acrolein-mediated genotoxicity.",
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T1 - Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5′-CpG-3′ sequence by the acrolein-derived γ-OH-1,N2-propano-2′-deoxyguanosine DNA adduct

AU - Cho, Young Jin

AU - Kim, Hye Young

AU - Huang, Hai

AU - Slutsky, Alvira

AU - Minko, Irina

AU - Wang, Hao

AU - Nechev, Lubomir V.

AU - Kozekov, Ivan D.

AU - Kozekova, Albena

AU - Tamura, Pamela

AU - Jacob, Jaison

AU - Voehler, Markus

AU - Harris, Thomas M.

AU - Lloyd, Robert (Stephen)

AU - Rizzo, Carmelo J.

AU - Stone, Michael P.

PY - 2005/12/21

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N2 - The interstrand N2,N2-dG DNA cross-linking chemistry of the acrolein-derived γ-OH-1,N2-propanodeoxyguanosine (γ-OH-PdG) adduct in the 5′-CpG-3′ sequence was monitored within a dodecamer duplex by NMR spectroscopy, in situ, using a series of site-specific 13C- and 15N-edited experiments. At equilibrium 40% of the DNA was cross-linked, with the carbinolamine form of the cross-link predominating. The cross-link existed in equilibrium with the non-crosslinked N2-(3-oxo-propyl)-dG aldehyde and its geminal diol hydrate. The ratio of aldehyde/diol increased at higher temperatures. The 1,N2-dG cyclic adduct was not detected. Molecular modeling suggested that the carbinolamine linkage should be capable of maintaining Watson-Crick hydrogen bonding at both of the tandem C-G base pairs. In contrast, dehydration of the carbinolamine cross-link to an imine (Schiff base) cross-link, or cyclization of the latter to form a pyrimidopurinone cross-link, was predicted to require disruption of Watson-Crick hydrogen bonding at one or both of the tandem cross-linked C-G base pairs. When the γ-OH-PdG adduct contained within the 5′-CpG-3′ sequence was instead annealed into duplex DNA opposite T, a mixture of the 1,N2-dG cyclic adduct, the aldehyde, and the diol, but no cross-link, was observed. With this mismatched duplex, reaction with the tetrapeptide KWKK formed DNA-peptide cross-links efficiently. When annealed opposite dA, γ-OH-PdG remained as the 1,N2-dG cyclic adduct although transient epimerization was detected by trapping with the peptide KWKK. The results provide a rationale for the stability of interstrand cross-links formed by acrolein and perhaps other αβ-unsaturated aldehydes. These sequence-specific carbinolamine cross-links are anticipated to interfere with DNA replication and contribute to acrolein-mediated genotoxicity.

AB - The interstrand N2,N2-dG DNA cross-linking chemistry of the acrolein-derived γ-OH-1,N2-propanodeoxyguanosine (γ-OH-PdG) adduct in the 5′-CpG-3′ sequence was monitored within a dodecamer duplex by NMR spectroscopy, in situ, using a series of site-specific 13C- and 15N-edited experiments. At equilibrium 40% of the DNA was cross-linked, with the carbinolamine form of the cross-link predominating. The cross-link existed in equilibrium with the non-crosslinked N2-(3-oxo-propyl)-dG aldehyde and its geminal diol hydrate. The ratio of aldehyde/diol increased at higher temperatures. The 1,N2-dG cyclic adduct was not detected. Molecular modeling suggested that the carbinolamine linkage should be capable of maintaining Watson-Crick hydrogen bonding at both of the tandem C-G base pairs. In contrast, dehydration of the carbinolamine cross-link to an imine (Schiff base) cross-link, or cyclization of the latter to form a pyrimidopurinone cross-link, was predicted to require disruption of Watson-Crick hydrogen bonding at one or both of the tandem cross-linked C-G base pairs. When the γ-OH-PdG adduct contained within the 5′-CpG-3′ sequence was instead annealed into duplex DNA opposite T, a mixture of the 1,N2-dG cyclic adduct, the aldehyde, and the diol, but no cross-link, was observed. With this mismatched duplex, reaction with the tetrapeptide KWKK formed DNA-peptide cross-links efficiently. When annealed opposite dA, γ-OH-PdG remained as the 1,N2-dG cyclic adduct although transient epimerization was detected by trapping with the peptide KWKK. The results provide a rationale for the stability of interstrand cross-links formed by acrolein and perhaps other αβ-unsaturated aldehydes. These sequence-specific carbinolamine cross-links are anticipated to interfere with DNA replication and contribute to acrolein-mediated genotoxicity.

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