Prediction of DNA structure from sequence: A build‐up technique

Hingerty, Brian E.; Figueroa, Samuel; Hayden, T. L.; Broyde, Suse

doi:10.1002/bip.360280703

Cited by 92 publications

(137 citation statements)

References 25 publications

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“…The starting structures for the unmodified DNA duplexes in both sequence contexts were energyminimized B-DNA structures computed with DUPLEX. 61 The initial models are shown in Fig. S8, Supplementary Data.…”

Section: Starting Structuresmentioning

confidence: 99%

Dynamics of a Benzo[a]pyrene-derived Guanine DNA Lesion in TGT and CGC Sequence Contexts: Enhanced Mobility in TGT Explains Conformational Heterogeneity, Flexible Bending, and Greater Susceptibility to Nucleotide Excision Repair

Cai

Patel

Geacintov

et al. 2007

Journal of Molecular Biology

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The nucleotide excision repair (NER) machinery excises a variety of bulky DNA lesions, but with varying efficiencies. The structural features of the DNA lesions that govern these differences are not well understood. An intriguing model system for studying structure-function relationships in NER is the major adduct derived from the reaction of the highly tumorigenic metabolite of benzo [a]pyrene, (+)-anti-benzo[a]pyrene diol epoxide, with the exocyclic amino group of guanine ((+)-trans-anti-[BP]-N 2 -dG, or G*). The rates of incision of the stereochemically identical lesions catalyzed by the prokaryotic UvrABC system was shown to be greater by a factor of 2.3±0.3 in the TG*T than in the CG*C sequence context [Biochemistry 46 (2007) 7006-7015]. Here we employ molecular dynamics simulations to elucidate the origin of the greater excision efficiency in the TG*T case and, more broadly, to delineate structural parameters that enhance NER. Our results show that the BP aromatic ring system is 5′-directed along the modified strand in the B-DNA minor groove in both sequence contexts. However, the TG*T modified duplex is much more dynamically flexible, featuring more perturbed and mobile Watson-Crick hydrogen bonding adjacent to the lesion, a greater impairment in stacking interactions, more dynamic local roll/ bending, and more minor groove flexibility. These characteristics explain a number of experimental observations concerning the (+)-trans-anti-[BP]-N 2 -dG adduct in double-stranded DNA with the TG*T sequence context: its conformational heterogeneity in NMR solution studies, its highly flexible bend, and its lower thermal stability. By contrast, the CG*C modified duplex is characterized by a single BP conformation and a rigid bend. While current recognition models of bulky lesions by NER factors have stressed the importance of impaired Watson-Crick pairing/ stacking and bending, our results highlight the likelihood of an important role for the local dynamics in the vicinity of the lesion.

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Section: Starting Structuresmentioning

confidence: 99%

Dynamics of a Benzo[a]pyrene-derived Guanine DNA Lesion in TGT and CGC Sequence Contexts: Enhanced Mobility in TGT Explains Conformational Heterogeneity, Flexible Bending, and Greater Susceptibility to Nucleotide Excision Repair

Cai

Patel

Geacintov

et al. 2007

Journal of Molecular Biology

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“…65,66 One was created from the basedisplaced-intercalative solution structure of the 10R (+)-cis-anti- [BP]G adduct, 30 by remodeling the 10R (+)-cis-anti isomer to the 10R (−)-trans-anti adduct (these two adducts differ from one another only by the absolute configurations at the C7, C8, and C9 carbon atoms, Figure 1), and by adding the methyl group to the 5-position of cytosine residue 5. The second model was created from the NMR solution structure of the minor groove 10R (−)-trans-anti- [BP]G adduct, 29 again by addition of the 5-methyl to cytosine residue 5 ( Figure 1).…”

Section: Molecular Mechanics Computationsmentioning

confidence: 99%

Methylation of Cytosine at C5 in a CpG Sequence Context Causes a Conformational Switch of a Benzo[a]pyrene diol epoxide-N2-guanine Adduct in DNA from a Minor Groove Alignment to Intercalation with Base Displacement

Zhang

Lin

Huang

et al. 2005

Journal of Molecular Biology

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It is well known that CpG dinucleotide steps in DNA, which are highly methylated at the 5-position of cytosine (meC) in human tissues, exhibit a disproportionate number of mutations within certain codons of the p53 gene. There is ample published evidence indicating that the reactivity of guanine with anti-B[a]PDE (a metabolite of the environmental carcinogen benzo[a]pyrene) at CpG mutation hot spots is enhanced by the methylation of the cytosine residue flanking the target guanine residue on the 5′-side. In this work we demonstrate that such a methylation can also dramatically affect the conformational characteristics of an adduct derived HHS Public Access

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“…Restrained conformational searches were carried out with DUPLEX, a molecular mechanics program for nucleic acids that performs potential energy minimization in the reduced variable domain of torsional angle space (26). Full details of this approach are given in an earlier work (27).…”

Section: Molecular Mechanics Computationsmentioning

confidence: 99%

Solution structure of the 2-amino-1- methyl-6-phenylimidazo[4,5- b ]pyridine C8-deoxyguanosine adduct in duplex DNA

Brown

Hingerty

Guenther

et al. 2001

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

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The carcinogenic heterocyclic amine (HA) 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is formed during the cooking of various meats. To enable structure͞activity studies aimed at understanding how DNA damaged by a member of the HA class of compounds can ultimately lead to cancer, we have determined the first solution structure of an 11-mer duplex containing the C8-dG adduct formed by reaction with N-acetoxy-PhIP. A slow conformational exchange is observed in which the PhIP ligand either intercalates into the DNA helix by denaturing and displacing the modified base pair (main form) or is located outside the helix in a minimally perturbed B-DNA duplex (minor form). In the main base-displaced intercalation structure, the minor groove is widened, and the major groove is compressed at the lesion site because of the location of the bulky PhIP-N-methyl and phenyl ring in the minor groove; this distortion causes significant bending of the helix. The PhIP phenyl ring interacts with the phosphodiestersugar ring backbone of the complementary strand and its fast rotation with respect to the intercalated imidazopyridine ring causes substantial distortions at this site, such as unwinding and bulging-out of the strand. The glycosidic torsion angle of the [PhIP]dG residue is syn, and the displaced guanine base is directed toward the 3 end of the modified strand. This study contributes, to our knowledge, the first structural information on the biologically relevant HA class to a growing body of knowledge about how conformational similarities and differences for a variety of types of lesions can influence protein interactions and ultimately biological outcome.C onsumption of foods containing heterocyclic amines (HA) has been implicated in the etiology of human cancers, including cancer of the colon, lung, and breast (1-4). The mutagen 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) is the most mass abundant of the HAs, which are formed in meat and fish by the condensation of amino acids with creat(in)ine during cooking (5, 6). PhIP has been shown to induce tumors in several organs in rodents (7-9) and form DNA adducts, which are considered initiating events in chemical carcinogenesis (10,11). Treatment of cultured mammalian cells with PhIP results in predominantly single-base substitutions (12, 13). A Ϫ1 frame-shift hotspot also has been observed in a 5Ј-GGGA-3Ј sequence in the Apc gene of PhIP-induced rat colon tumors and in the lacI gene of rat mammary glands (14-16).The major DNA adduct formed in vivo, and the only one unequivocally identified to date, is derived from the binding of metabolically activated PhIP to the C8 position of guanine [C8-dG-PhIP {N2-(2Ј-deoxyguanosin-8-yl)-PhIP}; refs. 17 and 18]. The reactive form of PhIP, a nitrenium ion, arises as a consequence of N-hydroxylation, which is catalyzed primarily by cytochrome CYP1A2 in humans (19,20), followed by N:Osulfation or N:O-acetylation (21). Analysis of phage vectors containing a site-specific C8-dG-PhIP adduct replicated in mammalian cells...

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Prediction of DNA structure from sequence: A build‐up technique

Cited by 92 publications

References 25 publications

Dynamics of a Benzo[a]pyrene-derived Guanine DNA Lesion in TGT and CGC Sequence Contexts: Enhanced Mobility in TGT Explains Conformational Heterogeneity, Flexible Bending, and Greater Susceptibility to Nucleotide Excision Repair

Dynamics of a Benzo[a]pyrene-derived Guanine DNA Lesion in TGT and CGC Sequence Contexts: Enhanced Mobility in TGT Explains Conformational Heterogeneity, Flexible Bending, and Greater Susceptibility to Nucleotide Excision Repair

Methylation of Cytosine at C5 in a CpG Sequence Context Causes a Conformational Switch of a Benzo[a]pyrene diol epoxide-N2-guanine Adduct in DNA from a Minor Groove Alignment to Intercalation with Base Displacement

Solution structure of the 2-amino-1- methyl-6-phenylimidazo[4,5- b ]pyridine C8-deoxyguanosine adduct in duplex DNA

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