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. Author manuscript; available in PMC: 2011 Jul 20.
Published in final edited form as: Environ Mol Mutagen. 2010 Jul;51(6):625–634. doi: 10.1002/em.20599

DNA Cross-links Induced by trans-4-Hydroxynonenal

Hai Huang 1, Ivan D Kozekov 1, Albena Kozekova 1, Hao Wang 1, R Stephen Lloyd 2, Carmelo J Rizzo 1, Michael P Stone 1,*
PMCID: PMC3140422  NIHMSID: NIHMS214404  PMID: 20577992

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 inter-strand 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,N2-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,8R,11S) aldehyde orients in the 5′-direction, while the (6R,8S,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.

trans-4-Hydroxynonenal (HNE) is produced from the metabolism of membrane lipids [Benedetti et al., 1980]. It is the major peroxidation product of ω-6 polyunsaturated fatty acids in vivo [Esterbauer et al., 1991, Burcham, 1998]. Several routes for the formation of HNE from ω-6 polyunsaturated fatty acids have been described [Lee and Blair, 2000, Schneider et al., 2001, Schneider et al., 2008]. HNE exposures modulate gene expression, cell signaling, cell proliferation, and apoptosis [Parola et al., 1999, Poli and Schaur, 2000, Nakashima et al., 2003, West et al., 2004, West and Marnett, 2005, 2006, Dwivedi et al., 2007]. Human exposures are associated with oxidative stress, and HNE has been implicated in the etiologies of Alzheimer's disease [Sayre et al., 1997], Parkinson's disease [Yoritaka et al., 1996], arteriosclerosis [Napoli et al., 1997], and hepatic ischemia reperfusion injury [Yamagami et al., 2000].

HNE induces the SOS response in Escherichia coli [Benamira and Marnett, 1992]. Chromosomal aberrations are observed upon exposures in a variety of mammalian cells [Esterbauer et al., 1990, Eckl et al., 1993, Karlhuber et al., 1997, Eckl, 2003], including human lymphocytes [Emerit et al., 1991]. HNE is mutagenic in rodent [Cajelli et al., 1987] and human cells [Hussain et al. 2000]. Mammalian genotoxicity depends upon glutathione, which is chemoprotective against the formation of HNE-DNA adducts [Chung et al., 2005, Falletti et al., 2007, Yadav et al., 2008]. Michael addition of the N2-amino group of deoxyguanosine to HNE gives diastereomeric 1,N2-dG adducts (Chart 1) [Winter et al., 1986, Douki et al., 2004, Kowalczyk et al., 2004], which have been detected in cellular DNA [Yi et al., 1997, Chung et al., 2000, Wacker et al., 2000, Wacker et al., 2001, Chung and Zhang, 2002, Liu et al., 2006b, Pan et al., 2006]. These 1,N2-dG adducts bear exocyclic rings through the bonding of guanine N1 and N2 to the HNE moiety; Watson-Crick hydrogen bonding is not possible.

Chart 1.

Chart 1

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Formation of exocyclic 1,N2-dG adducts 2-5 by HNE.

Synthesis of Stereospecific HNE-Derived 1,N2-dG Adducts

The stereochemical designations of the 1,N2-dG addition products (2-5) have been established unambiguously through chemical synthesis [Wang and Rizzo, 2001]; the four stereoisomers have been incorporated individually into 5′-d(GCTAGCXAGTCC)-3′•5′-d(GGACTCGCTAGC)-3′, containing the 5′-CpG-3′ sequence, in which X denotes the HNE-dG adduct (Chart 2). The approach involves condensation of stereospecific 4-amino-5-hydroxy-1,2-decane-diols with the corresponding oligodeoxynucleotides containing O6-[(2-trimethylsilyl)-ethyl]-2-fluorohypoxanthine, followed by deprotection and oxidation [Wang et al., 2003].

Chart 2.

Chart 2

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A. Numbering scheme of the 5′-CpG-3′ duplexes containing stereospecific HNE-dG adducts (X denotes the HNE-derived 1,N2-dG adducts). B. Numbering scheme of the HNE-dG adducts.

Stereospecific Formation of DNA Cross-links

Interest in the cross-linking abilities of the stereoisomers of the HNE-derived 1,N2-dG Michael addition products (2-5) arose from studies of the corresponding 1,N2-dG adducts of acrolein and crotonaldehyde, which formed reversible inter-strand cross-links in this 5′-CpG-3′ sequence, comprised of carbinolamine-type linkages in equilibrium with trace amounts of imines [Stone et al., 2008]. For the crotonaldehyde-derived adduct, the 6R stereoisomer forms cross-links more efficiently than does the 6S stereoisomer [Kozekov et al., 2003]. Of the four HNE-dG adducts (2-5), only stereoisomer 3 possessing (6S,8R,11S) stereochemistry results in inter-strand cross-link formation [Wang et al., 2003]. The (6S,8R,11S) isomer of HNE possesses the same relative stereochemistry as the crotonaldehyde-derived 6R adduct [Kozekov et al., 2003, Stone et al., 2008] (the R vs. S designation at C6 is reversed for the HNE adducts as compared to the crotonaldehyde adducts). The formation of these enal-mediated cross-links is intrinsically slow in vitro, on the order of days for the acrolein-derived adduct and weeks for the crotonaldehyde-derived adduct [Kozekov et al., 2001, Kozekov et al., 2003]. For HNE, cross-link formation requires several months to reach equilibrium at 37 °C, in vitro [Wang et al., 2003]. Nevertheless, as compared to the acrolein- and crotonaldehyde-derived cross-links [Kozekov et al., 2003, Stone et al., 2008], adduct 3 forms high levels of cross-links, suggesting that once formed, the cross-links are stable [Wang et al., 2003].

Ring-Opening to N2-dG Aldehyde Adducts

Exocyclic adducts 2 or 3 epimerize at the C8 position; in nucleosides and single-stranded DNA equilibrium favors the ring-closed configuration with the trans arrangement of the C8 hydroxyl group and the C6 alkyl side chain. When either adduct 2 or 3 is placed opposite cytosine in DNA, re-arrangement to aldehydes 6 and 10 is favored (Chart 3) [Huang et al., 2008a]. The observation of the 1H NMR resonance at ∼9.7 ppm indicates the presence of the aldehyde species. Presumably, the ring-opened structures facilitate Watson-Crick hydrogen bonding.

Chart 3.

Chart 3

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Ring-opening chemistry of the HNE-derived exocyclic 1,N2-dG adducts 2 and 3 when placed opposite dC in duplex DNA.

Rearrangement to Cyclic Hemiacetals

In contrast to the acrolein- [de los Santos et al., 2001] and crotonaldehyde-induced [Cho et al., 2006b] 1,N2-dG adducts, at equilibrium in DNA the predominant forms of the ring-opened species arising from HNE-derived adducts 2 or 3 are not the aldehydes 6, 10 or aldehydrols. 1H NMR indicates the presence of only trace amounts of aldehydes 6 and 10. Instead, the NMR and mass spectrometry data indicate that cyclic hemiacetals 8 and 9, or 12 and 13, arising from adducts 2 or 3, respectively (Chart 3) [Huang et al., 2008a]. Starting from adduct 2, 1H NOE studies reveal that cyclic hemiacetal stereoisomer 9 (6R,8S,11R) is the predominant species at equilibrium, and stereoisomer 8 (6R,8R,11R) is the minor species. Likewise, starting from adduct 3, cyclic hemiacetal stereoisomer 13 (6S,8R,11S) is the major species, and stereoisomer 12 (6S,8S,11S) is the minor species. The favored stereochemistry of the cyclic hemiacetal presumably avoids steric repulsion from the large substituents [Huang et al., 2008a]. The formation of cyclic hemiacetals 12 and 13 (Chart 3) [Huang et al., 2008a] provides a plausible explanation as to the slow rate of cross-link formation by adduct 3 in the 5′-CpG-3′ sequence [Wang et al., 2003]. The cyclic hemiacetals 12 and 13 would mask the aldehyde 10 necessary for formation of the 5′-CpG-3′ cross-link.

Stereochemistry Modulates Cross-link Formation in the 5′-CpG-3′ Sequence

The inability of adduct 2 to form cross-links in the 5′-CpG-3′ sequence [Wang et al., 2003], despite the fact that it also undergoes ring-opening when placed opposite dC in DNA [Huang et al., 2008a], involves stereospecific differences in the orientations of cyclic hemiacetals 9 and 13 within the minor groove, which control the orientations of aldehyde 6 as compared to aldehyde 10. NMR studies indicate that the sequential NOE connectivity of both duplexes is complete for both the modified and complementary strands [Huang et al., 2008b]. NOE studies indicate that the tetrahydrofuran ring of stereoisomer 9 is directed in the 3′-direction, while the tetrahydrofuran ring of stereoisomer 13 is directed in the 5′-direction. The aliphatic chain of stereoisomer 9 exhibits NOEs with protons in the 5′-direction and the tetrahydrofuran subunit exhibits NOEs with protons in the 3′-direction. In contrast, the aliphatic chain of stereoisomer 13 exhibits NOEs with protons in the 3′-direction and the tetrahydrofuran subunit exhibits NOEs with protons in the 5′-direction. The presence of the aliphatic chain within the minor groove suggests that the rotation of the HNE-derived cyclic hemiacetals around the X7 N5-X7 C6 bond is restrained. Consequently, to the extent that the cyclic hemiacetals 9 and 13 open to unmask the aldehydes 6 and 10, the latter are anticipated to adopt similar orientations as the respective cyclic hemiacetals. In summary, the (6S,8R,11S) stereoisomer of the 1,N2-dG adduct 3 that exists predominantly as cyclic hemiacetal 13 is positioned to facilitate cross-linking in the 5′-CpG-3′ sequence. In contrast, the (6R,8S,11R) stereoisomer of the 1,N2-dG adduct 2 that exists predominantly as cyclic hemiacetal 9 is not positioned to facilitate cross-link formation. Molecular modeling of the respective aldehydes, 6 and 10, is consistent with this conclusion. Aldehyde 6 orients in the 3′-direction, whereas aldehyde 10 orients in the 5′-direction. Thus, aldehyde 10, arising from 1,N2-dG adduct 3, is predicted to be proximate to C6•G19 base pair, facilitating formation of the cross-link in the 5′-CpG-3′ sequence.

Comparison to Crotonaldehyde-Derived DNA Cross-links

The 6R-configuration of the crotonaldehyde-derived 1,N2-dG adduct produces more DNA cross-links than does the 6S-configuration [Kozekov et al., 2003]. The 6R stereochemistry of the crotonaldehyde-derived adduct corresponds to the (6S,8R,11S) stereochemistry of HNE-derived adduct 3. Thus, the cyclic hemiacetal arising from adduct 3 facilitates inter-strand cross-linking for the same reason that the 6R-crotonaldehyde-derived adduct does [Cho et al., 2006b]: it places the requisite aldehyde in the minor groove proximal to the cross-linking target in the 5′-CpG-3′ sequence. Similarly, for the 6S crotonaldehyde-derived 1,N2-dG adduct, the aldehyde orients towards the A8•T17 base pair, distal to the targeted C•G base pair [Cho et al., 2006a]. In contrast to HNE, crotonaldehyde is small with regard to the width of the minor groove, which allows the aldehydic form of the crotonaldehyde-derived 6S adduct re-orient toward the cross-linking target C6•G19 base pair. This probably explains why <5% cross-link has been observed for the crotonaldehyde-derived 6S adduct [Kozekov et al., 2003]. However, the reduced form of the 6S-crotonaldehyde-derived cross-link is less stable compared to the 6R-crotonaldehyde-derived cross-link [Cho et al., 2007], consistent with modeling studies [Cho et al., 2006b]. Therefore, small amounts of cross-links formed upon reorientation of cyclic hemiacetal 9 would be anticipated to induce a greater destabilization of the DNA, as compared to the crotonaldehyde-derived 6S adduct. Further structural analyses of the cross-link arising from the (6S,8R,11S) HNE-derived adducts 3, currently in progress, are of considerable interest.

Biological Implications

Since (6S,8R,11S) adduct 3 forms inter-strand cross-links in 5′-CpG-3′ DNA sequences in vitro [Wang et al., 2003], it is anticipated that it will also form these cross-links in vivo. Since they occur specifically at 5′-CpG-3′ sequences, only for (6S,8R,11S) HNE adduct 3, and are reversible, they are anticipated to be present at low levels in vivo, challenging the limits of detection by mass spectrometry [Ruan et al., 2006, Stout et al., 2006, Zhang et al., 2006, Goodenough et al., 2007, Zayas et al., 2007].

The genotoxic consequences arising from low levels of these cross-links may be of considerable significance. Human inter-strand cross-link repair seems to require the cooperation of multiple proteins belonging to different pathways, including nucleotide excision repair (NER), homologous recombination (HR), trans-lesion synthesis (TLS), double-strand break (DSB) repair, and the Fanconi anemia (FA) pathway [Kennedy and D'Andrea, 2005, Niedernhofer et al., 2005, Nojima et al., 2005, Mirchandani and D'Andrea, 2006, Noll et al., 2006, Patel and Joenje, 2007]. One HR-independent model for inter-strand cross-link repair utilizes endonucleases for strand incision surrounding the cross-link on one of the two DNA strands and trans-lesion polymerases for gap-filling replication past the cross-link site on the other strand [Wang et al., 2001, Zheng et al., 2003, Richards et al., 2005, Liu et al., 2006a, Sarkar et al., 2006, Shen et al., 2006]. In this repair model, the dually incised strand possesses sufficient mobility that a bypass DNA polymerase can strand displace the nucleotide patch that is 5′ to the lesion, then replicate past the ICL site to complete the repair gap-filling synthesis.

Because enal-mediated inter-strand cross-links are reversible, most studies to date have utilized saturated inter-strand N2-dG•N2-dG propano cross-links as models to address molecular mechanisms of repair. The saturated cross-link has been used to investigate processing by the XPF/ERCC1 heterodimer; the results suggest a role for XPF/ERCC1 in the processing of a double-strand break that could be created when the cross-link encounters the replication fork [Mu et al., 2000]. In E. coli, a mechanism has been proposed in which repair is initiated by NER followed by trans-lesion DNA synthesis (TLS) and completed through another round of NER [Kumari et al., 2008]. Thus, pol IV catalyzes TLS when the nucleotides that are 5′ to the cross-link are removed. The efficiency of TLS is further increased when the nucleotides 3′ to the cross-linked site are also removed. Moriya and co-workers have examined the repair of crotonaldehyde-derived N2-dG•N2-dG inter-strand cross-links following replication of site-specifically modified vectors in E. coli and mammalian cells [Liu et al., 2006a]. Their results suggest that the native cross-link partially reverts, but are consistent with earlier reports that NER is essential for inter-strand cross-link repair in E. coli [Cole, 1973, Berardini et al., 1997]. In human XPA cells, the reduced cross-link is removed, suggesting a repair pathway unique to higher eukaryotes that does not require damage recognition by NER [Liu et al., 2006a]. Minko et al. [Minko et al., 2008] have reported that a vector containing a model of the incised product following dual incision around the saturated N2-dG•N2-dG propano cross-link is replicated in mammalian cells. Human polymerase κ catalyzes accurate incorporation opposite this cross-link and also replicates beyond the lesion. The reversibility of these HNE-derived inter-strand cross-links, as noted by Liu et al. [Liu et al., 2006a] might reduce their ability to block DNA processing, in vivo. Cross-link reversion would be anticipated to target removal of the resulting bulky N2-dG adducts by nucleotide excision repair [Chung et al., 2003, Feng et al., 2003, Choudhury et al., 2004].

Site-specific mutagenesis in the mammalian COS-7 system shows that stereoisomers 2 and 3 of the HNE-derived 1,N2-dG adduct induce low levels of G→T transversions and G→A transitions, whereas stereoisomers 4 and 5 are inactive [Fernandes et al., 2003]. The re-arrangement of these adducts into the cyclic hemiacetals 8 and 9, and 12 and 13, respectively, provides a potential explanation for the low levels of mutations induced by adducts 2 and 3 in the COS-7 system. The cyclic hemiacetals are anticipated to facilitate Watson-Crick hydrogen bonding during replication bypass [Fernandes et al., 2003]. Similar explanations have been advanced to explain low levels of mutations induced by acrolein- [VanderVeen et al., 2001, Yang et al., 2001] and crotonaldehyde-induced 1,N2-dG adducts [Fernandes et al., 2005]. While modestly higher levels of mutations are observed for the crotonaldehyde-derived adducts [Stein et al., 2006], these probably correlate with modestly higher levels of the intact 1,N2-dG products in DNA [Cho et al., 2006b]. This correlates with the observation that significantly higher levels of G→T mutations are associated with the ring-closed 1,N2-dG adducts [Xing et al., 2007]. The chemically stable 1,N2-propano-dG (PdG) adduct exhibits significant mutagenicity [Moriya et al., 1994, Moriya et al., 1999]. Incorporation of PdG into DNA precludes Watson-Crick hydrogen bonding and results in structural [Kouchakdjian et al., 1989, Kouchakdjian et al., 1990, Singh et al., 1993, Weisenseel et al., 2002] and thermodynamic [Plum et al., 1992] perturbations.

Consistent with these observations, HNE causes G→T transversions at codon 249 of p53 in lymphoblastoid cells [Hussain et al., 2000], and HNE adducts preferentially form with dG in codon 249 in the p53 gene [Hu et al., 2002]. The mutational spectrum induced by HNE-dG adducts in the supF gene of shuttle vector pSP189 replicated in human cells also shows primarily G→T transversions, accompanied by G→A transitions [Feng et al., 2003]. On the other hand, the mutational spectrum induced by HNE in the lacZ gene of the single-stranded M13 phage transfected into wild type Escherichia coli reveals recombination events, C→T transitions, and lesser amounts of G→C and A→C transversions, and frameshift mutations [Kowalczyk et al., 2004].

The acrolein-derived 1,N2-dG adduct provides a block to replicative mammalian DNA polymerases, pol δ and pol ε [Kanuri et al., 2002]. Consequently, it seems that replicative polymerases will also be blocked by the larger HNE-derived 1,N2-dG adducts. In contrast, the sequential action of human pols ι and κ, Y-family polymerases facilitates error-free bypass of the (6S,8R,11R) and (6S,8R,11S) diastereomers of the 1,N2-dG HNE adduct [Wolfle et al., 2006]. In this case, pol ι inserts dCTP and to a lesser extent dTTP opposite the HNE adduct but is unable to further elongate the primer. Further extension is observed in the presence of pol κ, which elongates from a primer terminus C opposite the 1,N2-dG HNE adducts more efficiently than when T is opposite the adducts [Wolfle et al., 2006].

Summary

The (6R,8S,11R) and (6S,8R,11S) HNE-derived 1,N2-dG adducts 2 and 3 have been examined in an oligodeoxynucleotide containing the 5′-CpG-3′ sequence in which adduct 3, but not adduct 2, forms inter-strand cross-links. At equilibrium the predominant forms of the ring-opened species arising from adducts 2 or 3 are cyclic hemiacetals 8 and 9, or 12 and 13 (Chart 3) [Huang et al., 2008a]. Starting from adduct 2, cyclic hemiacetal stereoisomer 9 (6R,8S,11R) is the major species. Starting from adduct 3, cyclic hemiacetal stereoisomer 13 (6S,8R,11S) is the major species. The orientations of the cyclic hemiacetal groups within the minor groove differ. The tetrahydrofuran ring of cyclic hemiacetal 13, arising from adduct 3, orients in the 5′-direction toward base pair C6•G19, while the tetrahydrofuran ring of cyclic hemiacetal 9, arising from adduct 2 with (6R,8S,11R) stereochemistry, orients in the 3′-direction toward base pair A8•T17. Thus, adduct 3 with (6S,8R,11S) stereochemistry facilitates formation of inter-strand cross-links, whereas adduct 2 with (6R,8S,11R) stereochemistry, does not form inter-strand cross-links. Detailed structural studies of the cross-links are currently in progress.

Figure 1.

Figure 1

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The adducted regions of the oligodeoxynucleotide duplexes containing the 5′-CpX-3′ sequence, viewed from the minor grooves. A. Average refined structure emergent from rMD calculations of the duplex containing cyclic hemiacetal 8. B. Predicted structure, obtained by molecular mechanics calculations, of the duplex containing aldehyde 6. The dashed arrows indicate the spatial relationship between the reactive aldehyde carbon and the exocyclic amino nitrogen of cross-linking target G19 (7.1 Å). C. Average refined structure emergent from rMD calculations of the duplex containing cyclic hemiacetal 10. D. Predicted structure, obtained by molecular mechanics calculations, of the duplex containing aldehyde 7. The cyan sticks represent nucleotides. The blue sticks represent the two amino nitrogens of X7 and G19. The white, green, and red sticks represent hydrogens, carbons, and oxygens of the HNE moiety. The dashed arrows indicate the spatial relationship between the reactive aldehyde carbon and the exocyclic amino nitrogen of cross-linking target G19 (4.4 Å). Adopted with permission from Huang et al., Biochemistry 2008 47: 11457-11472. Copyright 2008 American Chemical Society.

Figure 2.

Figure 2

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Base stacking of the adduct region for oligodeoxynucleotide duplexes containing the 5′-CpX-3′ sequence. A. The duplex containing cyclic hemiacetal 8. Stacking of base pair C6•G19 above base pair X7•C18. B. The duplex containing cyclic hemiacetal 8. Stacking of base pair X7•C18 above base pair A8•T17. C. The duplex containing cyclic hemiacetal 10. Stacking of base pair C6•G19 above base pair X7•C18. D. The duplex containing cyclic hemiacetal 10. Stacking of base pair X7•C18 above base pair A8•T17. For both duplexes containing either cyclic hemiacetals 8 or 10, base pairs C6•G19, X7•C18, and A8•T17 adopt Watson-Crick pairing.

Chart 4. Formation of the inter-strand cross-link by HNE derived (6S,8R,11S) 1,N2-dG adduct.

Chart 4

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Acknowledgments

Dr. Markus Voehler assisted with NMR experiments. Drs. Constance M. Harris and Thomas M. Harris provided thoughtful comments regarding the chemistry of these adducts. Dr. Irina G. Minko consulted on the biology of HNE. This work was supported by NIH Grant ES05355 (I.D.K., R.S.L., C.J.R. and M.P.S.). The Vanderbilt University Center in Molecular Toxicology is supported by NIH grant P30 ES00267. Vanderbilt University and NIH Grant RR05805 provided additional funding for NMR instrumentation.

Abbreviations

HNE

trans-4-hydroxynonenal

HNE-dG

trans-4-hydroxynonenal derived deoxyguanosine adduct

NOESY

nuclear Overhauser effect spectroscopy

NOE

nuclear Overhauser effect

pol

DNA polymerase

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