Mammalian cell mutagenesis of the DNA adducts of vinyl chloride and crotonaldehyde

Fernandes, Priscilla H.; Kanuri, Manorama; Nechev, Lubomir V.; Harris, Thomas M.; Lloyd, R. Stephen

doi:10.1002/em.20117

Cited by 56 publications

(50 citation statements)

References 27 publications

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“…47 Our post-synthetic modification strategy 48 allowed preparation of various dG enal adducts from a single modified phosphoramidite. A challenge was the preparation of stereochemically-defined amino diols for the crotonaldehyde (31,32) and 4-HNE adducts (33)(34)(35)(36) (Figure 2). [49][50][51][52] This strategy could not be applied to oligodeoxynucleotides containing α-OH-PdG (10), which were prepared using the modified phosphoramidite 25.…”

Section: Synthesis Of Oligodeoxynucleotides Containing 1n 2 -Dg Enalmentioning

confidence: 99%

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

et al. 2008

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ConspectusSignificant levels of the 1,N 2 -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 exposure. They yield interstrand DNA cross-links between guanines in the neighboring C•G 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,N 2 -γ-hydroxypropano-dG adduct. The stereochemistry at this center modulates the orientation of the reactive aldehyde within the minor groove of the doublestranded 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. IntroductionThe α,β-unsaturated aldehydes (enals) acrolein, crotonaldehyde, and 4-hydroxynonenal (4-HNE) (Scheme 1) are endogenous byproducts of lipid peroxidation, arising as a consequence of oxidative stress. [1][2][3][4] Acrolein and crotonaldehyde exposures also occur from exogenous sources, e.g., cigarette smoke 5 and automobile exhaust. 6 Enals react with DNA nucleobases to give exocyclic adducts; they also react with proteins. 7 Addition of enals to dG involves Michael addition of the N 2 -amine to give N 2 -(3-oxopropyl)-dG adducts (1, 3-8), followed by * Michael P. Stone telephone, 615-322-2589; fax, 615-322-7591; michael.p The lipid peroxidation product 4-HNE afforded related dGadducts (13-16). 14 Identification of acrolein adducts of other nucleosides followed. 15,16 The principal acrolein adduct is γ-OH-PdG (9), 10,12 although the regioisomeric 6-hydroxypyrimido[1,2-a]purin-10(3H)-one (α-OH-PdG, 10) has also been observed. 12,17 The γ-OH-PdG adduct (9) exists as a mixture of C8-OH epimers. With crotonaldehyde, addition at N 2 -dG creates a stereocenter at C6. Of four possible products, the two with the trans relative configurations at C6 and C8 (11,12) are observed. 12,18 These are also formed through the reaction of dG with two equivalents of acetaldehyde. 5,19,20 The cor...

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Section: Synthesis Of Oligodeoxynucleotides Containing 1n 2 -Dg Enalmentioning

confidence: 99%

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

et al. 2008

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“…TLS across the monoadducts has been characterized in human cells (22) and simian kidney cells (29). The study with human cells (22) reported that the S monoadduct was more miscoding than was the R monoadduct (10% vs 5%).…”

Section: Translesion Events Across Authentic and Model Iclsmentioning

confidence: 99%

Replication-Coupled Repair of Crotonaldehyde/Acetaldehyde-Induced Guanine−Guanine Interstrand Cross-Links and Their Mutagenicity

et al. 2006

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The repair of acetaldehyde/crotonaldehyde-induced guanine(N 2 )-guanine(N 2 ) interstrand cross-links (ICLs), 3-(2-deoxyribos-1-yl)-5,6,7,8-(N 2 -deoxyguanosyl)-6(R or S)-methyl-pyrimido [1,2-α] purine-10(3H)one (Scheme 1), was studied using a shuttle plasmid bearing a site-specific ICL. Since the authentic ICLs can revert to monoadducts, a chemically stable model ICL, 1,3-bis(2′-deoxyguanos-N 2 -yl)butane derivative, was also employed to probe the ICL repair mechanism. Since the removal of ICL depends on the nucleotide excision repair (NER) mechanism in Escherichia coli, the plasmid bearing the model ICL failed to yield transformants in NER-deficient host cells, proving the stability of this ICL in cells. The authentic ICLs yielded transformants in the NERdeficient hosts; therefore, these transformants are produced by plasmid bearing spontaneously reverted monoadducts. In contrast, in NER-deficient human cells, the model ICL was removed by an NER-independent repair pathway, which is unique to higher eukaryotes. This repair did not associate with a transcriptional event, but with replication. The analysis of repaired molecules revealed that the authentic and model ICLs were repaired mostly (>94 %) in an error-free manner in both hosts. The major mutations observed were G→T transversions targeting the cross-linked dG located in the lagging strand template. These results support one of the current models for the mammalian NER-independent ICL repair mechanism, in which a DNA endonuclease(s) unhooks an ICL from the leading strand template at a stalled replication fork site by incising on both sides of the ICL and then translesion synthesis is conducted across the "half-excised" ICL attached to the lagging strand template to restore DNA synthesis.Acetaldehyde is ubiquitous in the human environment (1). It is the major metabolite of ethanol and occurs widely in the diet. It is a common environmental pollutant and one of the most prevalent carcinogens in cigarette smoke (2). Crotonaldehyde also occurs in the human environment and in cigarette smoke, and is a product of lipid peroxidation (3-5). These chemicals are genotoxic carcinogens (1,3). DNA adduct formation is considered to be critical in their mechanisms of carcinogenesis. They react with DNA to form Interstrand cross-links (ICLs) 1 in 5′CpG sequence, as illustrated in Scheme 1, and other adducts (6). Similar ICLs † This study was supported by U.S. Public Health Service Grants ES11297, CA76163 and CA47995. ICLs are one of the most serious types of damage to DNA since they connect two strands of DNA covalently and thereby inhibit DNA strand separation required for various important processes such as replication, transcription and recombination. In Escherichia coli, the combined action of nucleotide excision repair (NER) and recombination or translesion synthesis (TLS) has been proposed for the repair of ICLs (reviewed in 11), in which NER incises one strand on both sides of an ICL to unhook from one strand and then the gap generated is filled by recomb...

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“…Soc. 125,[50][51][52][53][54][55][56][57][58][59][60][61]. Molecular dynamics calculations, restrained by NOE-based distances and empirical restraints, revealed that both the 5′-Cp-N 2 -dG-3′-R-(R)-CH 3 -propyl-5′-Cp-N 2 -dG-3′ and 5′-Cp-N 2 -dG-3′-S-(R)-CH 3 -propyl-5′-Cp-N 2 -dG-3′ cross-links were located in the minor groove and retained Watson-Crick hydrogen bonds at the tandem cross-linked C‚G base pairs.…”

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Stereochemistry Modulates the Stability of Reduced Interstrand Cross-Links Arising from R- and S-α-CH₃-γ-OH-1,N²-Propano-2‘-deoxyguanosine in the 5‘-CpG-3‘ DNA Sequence

et al. 2007

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The solution structures of 5'-Cp-N2-dG-3'-R-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' and 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' interstrand DNA cross-links in the 5'-CpG-3' sequence were determined by NMR spectroscopy. These were utilized as chemically stable surrogates for the corresponding carbinolamine interstrand cross-links arising from the crotonaldehyde- and acetaldehyde-derived R- and S-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adducts. The results provide an explanation for the observation that interstrand cross-link formation in the 5'-CpG-3' sequence by the R- and S-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adducts is dependent upon stereochemistry, favoring the R-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adduct [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50-61]. Molecular dynamics calculations, restrained by NOE-based distances and empirical restraints, revealed that both the 5'-Cp-N2-dG-3'-R-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' and 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-links were located in the minor groove and retained Watson-Crick hydrogen bonds at the tandem cross-linked C.G base pairs. However, for the 5'-Cp-N2-dG-3'-R-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-link, the (alpha)-CH3 group was positioned in the center of the minor groove, whereas for the 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-link, the (alpha)-CH3 group was positioned in the 3' direction, showing steric interference with the DNA helix. The 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-link exhibited a lower thermal stability as evidenced by NMR spectroscopy as a function of temperature. The two cross-links also exhibited apparent differences in the conformation of the interstrand three-carbon cross-link, which may also contribute to the lower apparent thermodynamic stability of the 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-link.

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Mammalian cell mutagenesis of the DNA adducts of vinyl chloride and crotonaldehyde

Cited by 56 publications

References 27 publications

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

Replication-Coupled Repair of Crotonaldehyde/Acetaldehyde-Induced Guanine−Guanine Interstrand Cross-Links and Their Mutagenicity

Stereochemistry Modulates the Stability of Reduced Interstrand Cross-Links Arising from R- and S-α-CH₃-γ-OH-1,N²-Propano-2‘-deoxyguanosine in the 5‘-CpG-3‘ DNA Sequence

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Mammalian cell mutagenesis of the DNA adducts of vinyl chloride and crotonaldehyde

Cited by 56 publications

References 27 publications

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

Replication-Coupled Repair of Crotonaldehyde/Acetaldehyde-Induced Guanine−Guanine Interstrand Cross-Links and Their Mutagenicity

Stereochemistry Modulates the Stability of Reduced Interstrand Cross-Links Arising from R- and S-α-CH3-γ-OH-1,N2-Propano-2‘-deoxyguanosine in the 5‘-CpG-3‘ DNA Sequence

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Stereochemistry Modulates the Stability of Reduced Interstrand Cross-Links Arising from R- and S-α-CH₃-γ-OH-1,N²-Propano-2‘-deoxyguanosine in the 5‘-CpG-3‘ DNA Sequence