NMR Solution Structure of a Nonanucleotide Duplex with a dG Mismatch Opposite a 10S Adduct Derived from Trans Addition of a Deoxyadenosine N6-Amino Group to (+)-(7R,8S,9S,10R)-7,8-Dihydroxy-9,10-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene: An Unusual syn Glycosidic Torsion Angle at the Modified dA

Yeh, Herman J. C.; Sayer, Jane M.; Liu, Xiaohong; Altieri, Amanda S.; Byrd, R. Andrew; Lakshman, Mahesh K.; Yagi, Haruhiko; Schurter, Eric J.; Gorenstein, David G.; Jerina, D. M.

doi:10.1021/bi00041a037

Cited by 71 publications

(158 citation statements)

References 40 publications

(60 reference statements)

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“…Although there are cases in which the adduct interacts with the minor (12, 13) or the major groove (14,15) of the double helix, in most cases the interaction occurs through intercalation between the surrounding base pairs (13, 16 -32). In many cases, the intercalation occurs from the major groove side (21,27,(31)(32)(33), resembling the conformation adopted by the cholesterol adducts studied in this paper. Displacement of the opposite base out of the helix is rather common, and in many cases the unpaired base is shifted toward the major groove.…”

Section: Molecular Recognition Properties Of the Damaged Dnas-mentioning

confidence: 66%

Effect of Bulky Lesions on DNA

Gómez‐Pinto

Cubero

Kalko

et al. 2004

Journal of Biological Chemistry

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The three-dimensional solution structure of two DNA decamers of sequence d(CCACXGGAAC)-(GTTCCG-GTGG) with a modified nucleotide containing a cholesterol derivative (X) in its C1(chol)␣ or C1(chol)␤ diastereoisomer form has been determined by using NMR and restrained molecular dynamics. This DNA derivative is recognized with high efficiency by the UvrB protein, which is part of the bacterial nucleotide excision repair, and the ␣ anomer is repaired more efficiently than the ␤ one. The structures of the two decamers have been determined from accurate distance constraints obtained from a complete relaxation matrix analysis of the NOE intensities and torsion angle constraints derived from J-coupling constants. The structures have been refined with molecular dynamics methods, including explicit solvent and applying the particle mesh Ewald method to properly evaluate the long range electrostatic interactions. These calculations converge to well defined structures whose conformation is intermediate between the A-and B-DNA families as judged by the root mean square deviation but with sugar puckerings and groove shapes corresponding to a distorted B-conformation. Both duplex adducts exhibit intercalation of the cholesterol group from the major groove of the helix and displacement of the guanine base opposite the modified nucleotide. Based on these structures and molecular dynamics calculations, we propose a tentative model for the recognition of damaged DNA substrates by the UvrB protein.DNA is susceptible to a number of lesions, such as those caused by chemicals, ionizing radiation, and ultraviolet light.Failure to repair DNA damage is thought to play a significant role in cancer and aging. Nucleotide excision repair (NER) 1 is a universal DNA repair mechanism that recognizes and removes many structurally diverse DNA lesions. This system repairs the damage in the DNA by a three step mechanism: (i) recognition of the lesion, (ii) dual nicking (3Ј and 5Ј) of the damaged strand around the altered site, and (iii) DNA synthesis and ligation to fill the 12-13-base gap. The NER system in eucaryotes is very complex and involves the action of at least 16 different polypeptides (1). On the contrary, in procaryotic organisms the NER mechanism involves only four specific proteins, UvrA, UvrB, UvrC, and UvrD (in addition to DNA polymerase and ligase). Despite the fact that the general mechanism of the UvrABCD system is known, many key issues remain unclear. The most important one is the determination of the structural characteristics of DNA lesions that trigger the repair system. The wide range of lesions that are recognized by the UvrABCD system suggests that the feature that induces repair is an alteration of the structural characteristics of the damaged DNA rather than a particular chemical structure of the damaging agent (2-4). After the analysis of a large number of lesions that are substrates of the UvrABCD system, van Houten (3) classified them into six categories: (i) covalent damage, (ii) bulky substituents, (iii) localize...

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Section: Molecular Recognition Properties Of the Damaged Dnas-mentioning

confidence: 66%

Effect of Bulky Lesions on DNA

Gómez‐Pinto

Cubero

Kalko

et al. 2004

Journal of Biological Chemistry

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“…5 Intercalative interactions between DNA duplexes and planar polycyclic aromatic organic intercalators, 5-6 such as ethidium bromide; acridine and its derivatives, and benzo[a]pyrene (BP), 7 have been thoroughly studied. Studies of bulky intercalators are rare.…”

Section: Introductionmentioning

confidence: 99%

Metal Complexes as DNA Intercalators

2011

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CONSPECTUSIntercalation was first proposed by Lerman in 1961 to explain the strong affinity of DNA for heterocyclic aromatic dyes and has attracted considerable attention as a mode of DNA binding ever since. Organic intercalators can inhibit nucleic acid synthesis in vivo and are common anticancer drugs used in clinical therapy. There are two major intercalation modes: classical and threading intercalation.We focus here on metallointercalators. Arene-nucleobase stacking interactions can have a significant influence on both the kinetics and thermodynamics of DNA binding. In particular, the cytotoxic activity of these complexes, conformational distortions, recognition by DNA-binding proteins and repair mechanisms are dependent on the arene. These complexes are non-cross-resistant with cisplatin towards cancer cells, and constitute a new class of anticancer agents with a different mechanism of action as compared to the anticancer drug cisplatin and its analogs. Cross-resistance is a phenomenon whereby a cell which is resistant to one drug is also resistant to another drug in the same class.Ruthenium-arene complexes with dual functions are more potent towards cancer cells than their non-intercalating analogs.In this Account, we focus on recent studies of dual function organometallic Ru II and Os II arene complexes and the methods used to detect arene-DNA intercalation.We relate these interactions to the mechanism of anticancer activity and to 3 structure-activity relationships. The interactions between these complexes and DNAshow close similarities to those of covalent polycyclic aromatic carcinogens, especially to N7-alkylating-intercalation compounds. However, Ru-arene complexes exhibit some new features. Classical intercalation and base extrusion next to the metallated base is observed for {(η 6 -biphenyl)Ru(ethylenediamine)} 2+ adducts of a 14-mer duplex, while penetrating arene intercalation occurs for adducts of the non-aromatic bulky intercalator {(η 6 -tetrahydroanthracene)Ru(ethylenediamine)} 2+ with a 6-mer duplex. The introduction of dual function ruthenium-arene complexes introduces new mechanisms of antitumor activity, novel mechanisms for attack on DNA, and new concepts for developing structure-activity relationships. We hope this discussion will stimulate thoughtful and focused research on the design of anticancer chemotherapeutic agents using these unique approaches.4

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“…BaP DE-dG trans adducts occupy the minor groove, with the hydrocarbon moiety of the 10R and 10S adducts oriented in opposite directions relative to the helix axis (toward the 3Ј and 5Ј ends of the modified strand, respectively) and do not significantly distort the double helix of B-form DNA (28 -30). In contrast, both cis (31) and trans (32)(33)(34)(35) opened dA adducts intercalate between base pairs such that the aromatic moiety of the 10R adducts inserts on the 5Ј side of the adducted base, whereas the aromatic moiety of the 10S adducts inserts on the 3Ј side. Based on the NMR structures, intercalation of the hydrocarbon results in buckling and twisting of the base pairs in the immediate vicinity of the adduct as well as local unwinding and overall bending of the helix axis.…”

mentioning

confidence: 99%

Inhibition of Werner Syndrome Helicase Activity by Benzo[a]pyrene Diol Epoxide Adducts Can Be Overcome by Replication Protein A

Choudhary

Doherty

Handy

et al. 2006

Journal of Biological Chemistry

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RecQ helicases are believed to function in repairing replication forks stalled by DNA damage and may also play a role in the intra-S-phase checkpoint, which delays the replication of damaged DNA, thus permitting repair to occur. Since little is known regarding the effects of DNA damage on RecQ helicases, and because the replication and recombination defects in Werner syndrome cells may reflect abnormal processing of damaged DNA associated with the replication fork, we examined the effects of specific bulky, covalent adducts at N 6 of deoxyadenosine (dA) or N 2 of deoxyguanosine (dG) on Werner (WRN) syndrome helicase activity. The adducts are derived from the optically active 7,8-diol 9,10-epoxide (DE) metabolites of the carcinogen benzo[a]pyrene (BaP). The results demonstrate that WRN helicase activity is inhibited in a strand-specific manner by BaP DE-dG adducts only when on the translocating strand. These adducts either occupy the minor groove without significant perturbation of DNA structure (trans adducts) or cause base displacement at the adduct site (cis adducts). In contrast, helicase activity is only mildly affected by intercalating BaP DE-dA adducts that locally perturb DNA double helical structure. This differs from our previous observation that intercalating dA adducts derived from benzo[c]phenanthrene (BcPh) DEs inhibit WRN activity in a strand-and stereospecific manner. Partial unwinding of the DNA helix at BaP DE-dA adduct sites may make such adducted DNAs more susceptible to the action of helicase than DNA containing the corresponding BcPh DE-dA adducts, which cause little or no destabilization of duplex DNA. The single-stranded DNA binding protein RPA, an auxiliary factor for WRN helicase, enabled the DNA unwinding enzyme to overcome inhibition by either the trans-R or cis-R BaP DE-dG adduct, suggesting that WRN and RPA may function together to unwind duplex DNA harboring specific covalent adducts that otherwise block WRN helicase acting alone.DNA damage evokes a cellular response by a genome surveillance system that senses DNA structural perturbation at the site of the lesion and elicits an appropriate response that may involve direct repair of the lesion, stabilization of the replication fork, or induction of apoptosis (1).Cellular pathways of DNA metabolism are influenced by DNA lesions, and since DNA unwinding enzymes known as helicases are among the first proteins to encounter DNA damage, it is of interest to understand how helicase action is modulated by interaction with chemically modified DNA. Although the mechanism for DNA unwinding has been studied for several helicases (2-4), only limited information is available regarding how specific covalently linked adducts affect helicase function. Of particular interest to us has been the Werner (WRN) 3 helicase that is defective in the premature aging and genome instability disorder Werner syndrome (WS) (5). The WRN helicase belongs to the RecQ family of Superfamily 2 DNA helicases (5) and has been shown to unwind double-stranded DNA in a 3Ј t...

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NMR Solution Structure of a Nonanucleotide Duplex with a dG Mismatch Opposite a 10S Adduct Derived from Trans Addition of a Deoxyadenosine N6-Amino Group to (+)-(7R,8S,9S,10R)-7,8-Dihydroxy-9,10-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene: An Unusual syn Glycosidic Torsion Angle at the Modified dA

Cited by 71 publications

References 40 publications

Effect of Bulky Lesions on DNA

Effect of Bulky Lesions on DNA

Metal Complexes as DNA Intercalators

Inhibition of Werner Syndrome Helicase Activity by Benzo[a]pyrene Diol Epoxide Adducts Can Be Overcome by Replication Protein A

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