Adduction of the Human N-ras Codon 61 Sequence with (−)-(7S,8R,9R,10S)-7,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene:  Structural Refinement of the Intercalated SRSR(61,2) (−)-(7S,8R,9S,10R)-N6-[10-(7,8,9,10-Tetrahydrobenzo[a]pyrenyl)]-2‘-deoxyadenosyl Adduct from 1H NMR

Zegar, Irene S.; Kim, Seong J.; Johansen, Tommy N.; Horton, Pamela; Harris, Constance M.; Harris, Thomas M.; Stone, Michael P.

doi:10.1021/bi9524732

Cited by 77 publications

(162 citation statements)

References 67 publications

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“…20,21 The 10R(Ϫ)-trans-anti adduct structure shown is essentially the same as that of the NMR solution structure of Zegar et al 22 determined in the same C[A*]A sequence context of codon 61 of the human N-ras gene.…”

Section: Adduct Structuressupporting

confidence: 66%

Thermodynamic and structural factors in the removal of bulky DNA adducts by the nucleotide excision repair machinery

et al. 2002

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The function of the human nucleotide excision repair (NER) apparatus is to remove bulky adducts from damaged DNA. In an effort to gain insights into the molecular mechanisms involved in the recognition and excision of bulky lesions, we investigated a series of site specifically modified oligonucleotides containing single, well-defined polycyclic aromatic hydrocarbon (PAH) diol epoxide-adenine adducts. Covalent adducts derived from the bay region PAH, benzo[a]pyrene, are removed by human NER enzymes in vitro. In contrast, the stereochemically analogous N(6)-dA adducts derived from the topologically different fjord region PAH, benzo[c]phenanthrene, are resistant to repair. The evasion of DNA repair may play a role in the observed higher tumorigenicity of the fjord region PAH diol epoxides. We are elucidating the structural and thermodynamic features of these adducts that may underlie their marked distinction in biologic function, employing high-resolution nuclear magnetic resonance studies, measurements of thermal stabilities of the PAH diol epoxide-modified oligonucleotide duplexes, and molecular dynamics simulations with free energy calculations. Our combined findings suggest that differences in the thermodynamic properties and thermal stabilities are associated with differences in distortions to the DNA induced by the lesions. These structural effects correlate with the differential NER susceptibilities and stem from the intrinsically distinct shapes of the fjord and bay region PAH diol epoxide-N(6)-adenine adducts.

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Section: Adduct Structuressupporting

confidence: 66%

Thermodynamic and structural factors in the removal of bulky DNA adducts by the nucleotide excision repair machinery

et al. 2002

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“…This adenine adduct of BPDE provides a distinct structural theme characterized by intercalative carcinogen insertion without displacement of the modified base pair, although the respective hydrogen bonds are destabilized more severely than in the trans-BPDE-N 2 -dG counterparts (57). Presumably because of these gradual differences in the extent of base pair disruption, the (Ϫ)-trans-BPDE-N 6 -dA adduct in the N-ras codon 61 sequence is excised in vitro at a slightly faster rate than the trans-BPDE-N 2 -dG adducts tested in this study.…”

Section: Discussionmentioning

confidence: 99%

Base Pair Conformation-Dependent Excision of Benzo[a]Pyrene Diol Epoxide-Guanine Adducts by Human Nucleotide Excision Repair Enzymes

Heß

Gunz

Luneva

et al. 1997

Molecular and Cellular Biology

160

220

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by benzo[a]pyrene diol epoxide (BPDE), a potent and ubiquitous mutagen that induces mainly G ⅐ C3T ⅐ A transversions and frameshift deletions. We found that human nucleotide excision repair processes the predominant (؉)-trans-BPDE-N 2 -dG adduct 15 times less efficiently than a standard acetylaminofluorene-C 8 -dG lesion in the same sequence. No difference was observed between (؉)-trans-and (؊)-trans-BPDE-N 2 -dG, but excision was enhanced about 10-fold by changing the adduct configurations to either (؉)-cis-or (؊)-cis-BPDE-N 2 -dG. Conversely, excision of (؉)-cis-and (؊)-cis-but not (؉)-trans-BPDE-N 2 -dG was reduced about 10-fold when the complementary cytosine was replaced by adenine, and excision of these BPDE lesions was essentially abolished when the complementary deoxyribonucleotide was missing. Thus, a set of chemically identical BPDE adducts yielded a greater-than-100-fold range of repair rates, demonstrating that nucleotide excision repair activity is entirely dictated by local DNA conformation. In particular, this unique comparison between structurally highly defined substrates shows that fast excision of BPDE-N 2 -dG lesions is correlated with displacement of both the modified guanine and its partner base in the complementary strand from their normal intrahelical positions. The very slow excision of carcinogen-DNA adducts located opposite deletion sites reveals a cellular strategy that minimizes the fixation of frameshifts after mutagenic translesion synthesis.Mammalian nucleotide excision repair promotes genomic stability by removing UV radiation products and a wide range of chemical carcinogen-DNA adducts (14,20,37,42,52). This multisubunit DNA repair system operates by cleavage of damaged strands on either side of the targeted lesion (28, 35) followed by excision of oligonucleotide segments 24 to 32 residues in length (25,31). In subsequent reactions, double-helical integrity and the correct nucleotide sequence are reestablished by DNA repair synthesis and DNA ligation (1, 40).The mechanism by which mammalian nucleotide excision repair enzymes discriminate damaged sites as substrates for dual DNA incision is not understood (14,24,26,42), but several reports have demonstrated that excision activity is highly nonuniform in the context of mammalian chromosomes. For example, bulky UV radiation products are excised at variable rates, with cyclobutane pyrimidine dimers being processed considerably more slowly than the less frequently occurring pyrimidine(6-4)pyrimidone lesion (30). Generally, active genes are repaired faster than inactive loci, and the template strand of RNA polymerase II-transcribed genes is repaired faster than the coding strand (2,3,20,29,46). Yet another level of heterogeneity emerged when DNA excision repair rates were compared between closely related genomic sites. Along the nontranscribed strand of the human hypoxanthine phosphoribosyltransferase gene, for example, excision repair of guanine adducts formed by benzo[a]pyrene diol epoxide (BPDE) varies by more than 1 order of magni...

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“…Two structures were aligned: the NMR structure of a DNA duplex that contains a trans-10R BaP DE-2 dA adduct (BaP-DNA) (20) and the x-ray crystal structure of human top1 covalently complexed with a double-stranded DNA substrate (7). The unadducted strand of the BaP-DNA was aligned with the scissile DNA strand in the top1 covalent complex.…”

Section: Dnamentioning

confidence: 99%

“…trans-opened BaP DE-2 adducts at N 6 of dA were selected because several NMR studies have shown that such adducts intercalate into the DNA without significant disruption of the DNA structure, whereas the previously studied (15) trans-opened BaP DE-2 adducts at N 2 of dG lie in the minor groove (16). trans-R dA adducts are intercalated toward the 5Ј side of the modified base (17)(18)(19)(20)(21). Although the evidence is less compelling for trans-10S-BaP DE-2 dA adducts, such adducts are thought to intercalate toward the 3Ј side of their adducted base (22,23).…”

mentioning

confidence: 99%

Position-specific trapping of topoisomerase I–DNA cleavage complexes by intercalated benzo[ a ]- pyrene diol epoxide adducts at the 6-amino group of adenine

Pommier

Laco

Kohlhagen

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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DNA topoisomerase I (top1) is the target of potent anticancer agents, including camptothecins and DNA intercalators, which reversibly stabilize (trap) top1 catalytic intermediates (cleavage complexes). The aim of the present study was to define the structural relationship between the site(s) of covalently bound intercalating agents, whose solution conformations in DNA are known, and the site(s) of top1 cleavage. Two diastereomeric pairs of oligonucleotide 22-mers, derived from a sequence used to determine the crystal structure of top1-DNA complexes, were synthesized. One pair contained either a trans-opened 10R-or 10S-benzo[a]pyrene 7,8-diol 9,10-epoxide adduct at the N 6 -amino group of a central 2 -deoxyadenosine residue in the scissile strand, and the other pair contained the same two adducts in the nonscissile strand. These adducts were derived from the (؉)-(7R,8S,9S,10R)-and (؊)-(7S,8R,9R,10S)-7,8-diol 9,10-epoxides in which the benzylic 7-hydroxyl group and the epoxide oxygen are trans. On the basis of analogy with known solution conformations of duplex oligonucleotides containing these adducts, we conclude that top1 cleavage complexes are trapped when the hydrocarbon adduct is intercalated between the base pairs flanking a preexisting top1 cleavage site, or between the base pairs immediately downstream (3 relative to the scissile strand) from this site. We propose a model with the ؉1 base rotated out of the duplex, and in which the intercalated adduct prevents religation of the corresponding nucleotide at the 5 end of the cleaved DNA. These results suggest mechanisms whereby intercalating agents interfere with the normal function of human top1. D NA topoisomerase I (top1) is an essential enzyme in higher eukaryotes (1, 2). It can relax DNA supercoiling and relieve torsional strain during DNA processing, including replication, transcription, and repair. It can also perform intermolecular religation leading to DNA recombinations (3, 4). The catalytic intermediate of top1 is a cleavage complex in which a tyrosine (Tyr-723 for human top1) in the enzyme attacks a DNA phosphodiester and forms a covalent bond to the phosphorus at the 3Ј side of the cleavage site while a 5Ј-hydroxyl is generated at the other side (1, 2). The reaction occurs with short duplex oligodeoxynucleotides (5, 6), as evidenced by recent crystal structures of top1-DNA complexes (7,8).top1 is the cellular target of several anticancer drugs, including the camptothecins, which have recently been approved by the Food and Drug Administration for the treatment of colon and ovarian carcinomas. The anticancer activity of these drugs results from the trapping of top1 cleavage complexes such that the enzyme is reversibly inactivated as it cleaves DNA (9-11). These agents are often referred to as ''top1 poisons.'' They represent an exemplary case of pharmacological interference whereby the drug stabilizes the interactions of two macromolecules (i.e., top1 and DNA) by formation of a ternary complex. Because of the clinical efficacy of camptothecins, no...

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Adduction of the Human N-ras Codon 61 Sequence with (−)-(7S,8R,9R,10S)-7,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene: Structural Refinement of the Intercalated SRSR(61,2) (−)-(7S,8R,9S,10R)-N⁶-[10-(7,8,9,10-Tetrahydrobenzo[a]pyrenyl)]-2‘-deoxyadenosyl Adduct from ¹H NMR

Cited by 77 publications

References 67 publications

Thermodynamic and structural factors in the removal of bulky DNA adducts by the nucleotide excision repair machinery

Thermodynamic and structural factors in the removal of bulky DNA adducts by the nucleotide excision repair machinery

Base Pair Conformation-Dependent Excision of Benzo[a]Pyrene Diol Epoxide-Guanine Adducts by Human Nucleotide Excision Repair Enzymes

Position-specific trapping of topoisomerase I–DNA cleavage complexes by intercalated benzo[ a ]- pyrene diol epoxide adducts at the 6-amino group of adenine

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