Structural Studies of an Oligodeoxynucleotide Containing a Trimethylene Interstrand Cross-Link in a 5‘-(CpG) Motif: Model of a Malondialdehyde Cross-Link

Dooley, Patricia A.; Tsarouhtsis, Dimitrios; Korbel, Gregory A.; Nechev, Lubomir V.; Shearer, Jill; Zegar, Irene S.; Harris, Constance M.; Stone, Michael P.; Harris, Thomas M.

doi:10.1021/ja003163w

Cited by 58 publications

(117 citation statements)

References 45 publications

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“…Similar to the base pair substitutions, 15% of the MDA-induced insertions and deletions occurred within or immediately adjacent to a 5Ј-(CG) sequence. Thus, there is a correlation between the preferred cross-link sequence, structural data, and a subset of the observed mutation spectrum (57). MDA-induced mutations at sites other than 5Ј-(CG) may have arisen as a result of NER-dependent incision of sequences flanking the 5Ј-(CG) ICLs (59,60), through the intermediacy of cross-links at other sequences, or from other MDA-DNA adducts that trigger mutations in an NER-dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells

Niedernhofer

Daniels

Rouzer

et al. 2003

Journal of Biological Chemistry

484

324

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Section: Discussionmentioning

confidence: 99%

Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells

Niedernhofer

Daniels

Rouzer

et al. 2003

Journal of Biological Chemistry

484

324

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“…59 The saturated linkage caused minimal Interstrand cross-linking by γ-OH-PdG was specific to the 5′-CpG-3′ sequence (Figure 9). When γ-OH-PdG (9) was engineered into 5′-d(CGTACXCATGC)-3′, containing both the 5′-CpG-3′ or 5′-GpC-3′ sequences, 55 and the complement 5′-(GCATGCGTACG)-3′ was labeled with 15 N 2 -dG (the underlined corresponds to the potential 5′-CpG-3′ cross-link), only 15 Nlabeled bis-nucleoside cross-link 19 was observed after enzymatic digestion and analysis by LC-ESI-MS, establishing the 5′-CpG-3′ sequence dependence for cross-linking.…”

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

confidence: 98%

“…62 When the N 2 -dG:N 2 -dG trimethylene linkage (37), a surrogate for the non-observed cross-link in the 5′-GpC-3′ sequence, was constructed in d(TCCXCGGA) 2 , its structure was distorted, and its T m was reduced. 59,63 Interstrand Cross-linking of (6R) and (6S) Crotonaldehyde 1,N 2 -PdG AdductsRing-opening of the diastereomeric 1,N 2 -dG adducts 11 and 12 was incomplete at pH 7 when placed opposite dG in duplex DNA. The incomplete ring-opening was attributed to the positioning of the CH 3 groups to avoid steric clash with N3 of guanine, which becomes significant in the N 2 -(1-methyl-3-oxopropyl)-dG aldehydes (3,4).…”

mentioning

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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“…The 1 H NMR was complex and showed the presence of two diastereomers. 31 Enzymatic digestion reaction mixtures were analyzed on a Phenomenex Luna C18 column (250 Â 4.6 mm, 5 μm) using the same method. Mass spectra of oligonucleotides were recorded on a quadrupole ion trap LC mass spectrometer (Thermofinnigan, San Jose, CA) equipped with electrospray ionization.…”

Section: ' Conclusionmentioning

confidence: 99%

Unprecedented C-Selective Interstrand Cross-Linking through in Situ Oxidation of Furan-Modified Oligodeoxynucleotides

Beeck

Madder

2010

J. Am. Chem. Soc.

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Chemical reagents that form interstrand cross-links have been used for a long time in cancer therapy. They covalently link two strands of DNA, thereby blocking transcription. Cross-link repair enzymes, however, can restore the transcription processes, causing resistance to certain anti-cancer drugs. The mechanism of these cross-link repair processes has not yet been fully revealed. One of the obstacles in this study is the lack of sufficient amounts of well-defined, stable, cross-linked duplexes to study the pathways of cross-link repair enzymes. Our group has developed a cross-link strategy where a furan moiety is incorporated into oligodeoxynucleotides (ODNs). These furan-modified nucleic acids can form interstrand crosslinks upon selective furan oxidation with N-bromosuccinimide. We here report on the incorporation of the furan moiety at the 2 0 -position of a uridine through an amido or ureido linker. The resulting modified ODNs display an unprecedented selectivity for cross-linking toward a cytidine opposite the modified residue, forming one specific cross-linked duplex, which could be isolated in good yield. Furthermore, the structure of the formed cross-linked duplexes could be unambiguously characterized. ' INTRODUCTIONThe high specificity with which oligonucleotides recognize nucleic acids has led to considerable interest in the design of modified oligonucleotides. 1 These customized nucleic acid derivatives can be used for a range of therapeutic and analytical purposes, including the treatment of diseases (antisense, 2-4 siRNA 5-8 ), the regulation of gene expression (antigene, 9-11 decoy DNA 12,13 ), the investigation of RNA tertiary structures, 14-16 and the study of DNA damage and the resulting repair processes. [17][18][19][20][21] DNA is not indefinitely stable, and numerous sources of DNAdamaging agents of endogenous and exogenous origin contribute further to the instability of DNA. 22 DNA interstrand cross-links (ICLs) are among the most cytotoxic lesions known, the covalent bond between the two DNA strands prohibiting strand separation and thereby blocking vital aspects of DNA metabolism. ICLs are mostly formed by reaction of cellular DNA with bifunctional electrophilic compounds that are either formed endogenously (e.g., lipid peroxidation) or present through exogenous exposure. 23 Additionally, generation of an abasic site in the DNA upon depurination can also give rise to ICL formation. 20,24 The cytotoxic properties of such ICL-forming agents are exploited by cancer chemotherapeutics, where their toxicity ultimately leads to apoptosis of the malignant cells. 25 Development of resistance of the tumor cells to treatment with antitumor drugs can often be attributed to enhanced ICL repair. 23 These repair pathways find their evolutionary origin in the necessity to counteract the threat posed by endogenous and exogenous crosslinking compounds, and failure to repair these lesions can lead to inherited disorders such as Fanconi anemia. 23 Thus, although DNA repair is essential for a heal...

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Structural Studies of an Oligodeoxynucleotide Containing a Trimethylene Interstrand Cross-Link in a 5‘-(CpG) Motif: Model of a Malondialdehyde Cross-Link

Cited by 58 publications

References 45 publications

Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells

Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells

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

Unprecedented C-Selective Interstrand Cross-Linking through in Situ Oxidation of Furan-Modified Oligodeoxynucleotides

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