DNA Interchain Cross-Links Formed by Acrolein and Crotonaldehyde

Kozekov, Ivan D.; Nechev, Lubomir V.; Moseley, Michelle; Harris, Constance M.; Rizzo, Carmelo J.; Stone, Michael P.; Harris, Thomas M.

doi:10.1021/ja020778f

Cited by 175 publications

(268 citation statements)

References 39 publications

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“…It should be noted that the bypass activity of pol IV was not assessed in the above studies. In contrast, the acrolein-mediated ICLs used in this study are between the exocyclic amino groups of guanine residues in a CpG sequence context (17)(18)(19). This linkage is within the minor groove of DNA, and this difference may strongly dictate which polymerase might be capable of catalyzing TLS past specific ICLs.…”

Section: Discussionmentioning

confidence: 98%

Replication Bypass of Interstrand Cross-link Intermediates by Escherichia coli DNA Polymerase IV

Kumari

Minko

Harbut

et al. 2008

Journal of Biological Chemistry

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Repair of interstrand DNA cross-links (ICLs) in Escherichia coli can occur through a combination of nucleotide excision repair (NER) and homologous recombination. However, an alternative mechanism has been proposed in which repair is initiated by NER followed by translesion DNA synthesis (TLS) and completed through another round of NER. Using site-specifically modified oligodeoxynucleotides that serve as a model for potential repair intermediates following incision by E. coli NER proteins, the ability of E. coli DNA polymerases (pol) II and IV to catalyze TLS past N 2 -N 2 -guanine ICLs was determined. No biochemical evidence was found suggesting that pol II could bypass these lesions. In contrast, pol IV could catalyze TLS when the nucleotides that are 5 to the cross-link were removed. The efficiency of TLS was further increased when the nucleotides 3 to the cross-linked site were also removed. The correct nucleotide, C, was preferentially incorporated opposite the lesion. When E. coli cells were transformed with a vector carrying a site-specific N 2 -N 2 -guanine ICL, the transformation efficiency of a pol II-deficient strain was indistinguishable from that of the wild type. However, the ability to replicate the modified vector DNA was nearly abolished in a pol IV-deficient strain. These data strongly suggest that pol IV is responsible for TLS past N 2 -N 2 -guanine ICLs.Interstrand DNA cross-links (ICLs) 2 represent a major challenge to cellular survival by virtue of their ability to block progression of DNA replication and transcription. In Escherichia coli, biochemical and genetic data support a mechanism by which ICLs can be repaired through the combined activities associated with the nucleotide excision repair (NER) pathway and the homologous recombination (HR) damage avoidance pathway (1). The overall pathway requires recognition and initiation of ICL repair by the action of UvrABC, creating dual incisions by hydrolyzing the ninth phosphodiester bond 5Ј and the third phosphodiester bond 3Ј to the cross-link (2, 3). It has been proposed that this "unhooked" DNA can be structurally manipulated such that HR-driven strand invasion occurs via pairing with the intact strand that is still physically linked to the incised strand. Subsequent to recombination, in which a nondamaged homologous strand is positioned opposite the crosslinked strand, a second round of NER can excise the remaining damage, followed by gap synthesis and ligation.Although the above mechanism has the capacity to fully repair ICL-containing DNA, an alternative pathway not requiring HR has been proposed (4, 5). This pathway utilizes the activity of the polB gene product, DNA polymerase (pol) II. The data demonstrated that pol II, but not pol IV or V, was functioning in this HR-independent ICL repair pathway. It was hypothesized that pol II could catalyze replication bypass of the incised but still covalently linked DNA (4, 5). However, no biochemical data supporting such an activity of pol II have subsequently appeared.Using a series of synth...

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Section: Discussionmentioning

confidence: 98%

Replication Bypass of Interstrand Cross-link Intermediates by Escherichia coli DNA Polymerase IV

Kumari

Minko

Harbut

et al. 2008

Journal of Biological Chemistry

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“…After >20 days, ~40% cross-link formation occurred for the 6R diastereomer 11 (Figure 10), whereas < 5% cross-link was observed for the 6S diasteromer 12. 55 Digestion of the cross-link yielded the bis-nucleoside pyrimidopurinone, 55 identical to that isolated from acetaldehyde-treated DNA. 19 The presence of the imine linkage was inferred since the cross-link was reductively trapped.…”

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

confidence: 94%

“…55,56 A new species formed and reached a level of ~ 50% yield after seven days at 25 °C. Mass spectrometric analysis suggested the chemical nature of the cross-link was a carbinolamine linkage (17), in equilibrium with either or both the imine (18) or pyrimidopurinone (19) forms.…”

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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“…Recently, a liquid chromatography-electrospray ionization-tandem mass spectrometry method was recently developed [18]. It is reported that the γ-OH-Acr-dG adduct is biologically important in the formation of DNA-DNA, DNA-peptide and DNA-protein cross-links [19], whereas α-OH-Acr-dG does not form these cross-linked species, probably due to its inability to undergo ring-opening [20]. A previous study showed that α-OH-Acr-dG is more mutagenic and genotoxic than γ-OH-Acr-dG [21].…”

Section: Introductionmentioning

confidence: 99%

Detection of the acrolein-derived cyclic DNA adduct by a quantitative 32P-postlabeling/solid-phase extraction/HPLC method: Blocking its artifact formation with glutathione

Emami

Dyba

Cheema

et al. 2008

Analytical Biochemistry

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Acrolein (Acr), a hazardous air pollutant, reacts readily with deoxyguanosine (dG) in DNA to produce cyclic 1,N 2 -propanodeoxyguanosine adducts (Acr-dG). Studies show that these adducts are detected in vivo and may play a role in mutagenesis and carcinogenesis. In the present study, we developed a quantitative 32 P-postlabeling/solid phase extraction/HPLC method by optimizing the solid phase extraction and the 32 P-postlabeling conditions for analysis of Acr-dG in DNA samples with a detection limit of 0.1 fmole. Using this assay, we found Acr-dG can be formed as an artifact during the assay. We obtained evidence from mass spectrometry showing that Acr in water used in the assay is a likely source of artifact formation of Acr-dG. The formation of Acr-dG as an artifact can be effectively blocked by adding glutathione (GSH) to the DNA sample to be analyzed. In addition, we detected Acr-dG as a contaminant in the commercial dG and dT 3′-monophosphate samples. Finally, we applied this method to detect Acr-dG in calf thymus and human colon HT29 cell DNA with an excellent linear quantitative relationship.

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DNA Interchain Cross-Links Formed by Acrolein and Crotonaldehyde

Cited by 175 publications

References 39 publications

Replication Bypass of Interstrand Cross-link Intermediates by Escherichia coli DNA Polymerase IV

Replication Bypass of Interstrand Cross-link Intermediates by Escherichia coli DNA Polymerase IV

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

Detection of the acrolein-derived cyclic DNA adduct by a quantitative 32P-postlabeling/solid-phase extraction/HPLC method: Blocking its artifact formation with glutathione

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