NMR Solution Structures of Stereoisomeric Covalent Polycyclic Aromatic Carcinogen−DNA Adducts:  Principles, Patterns, and Diversity

Geacintov, Nicholas E.; Cosman, Monique; Hingerty, Brian E.; Amin, Shantu; Broyde, Suse; Patel, Dinshaw J.

doi:10.1021/tx9601418

Cited by 331 publications

(518 citation statements)

References 145 publications

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“…These lesions can produce mutations on replication in vitro and in vivo [74][75][76]. Such mutations, when present in DNA sequences that regulate the cell cycle, can trigger cancer initiation [72].…”

Section: Box 3 Benzo[a]pyrene-derived Dna Lesionsmentioning

confidence: 99%

“…The most tumorigenic benzo [77]; this metabolite reacts largely, but not exclusively, with the exocyclic amino group of guanine to produce the major 10S (+) trans-anti-BP-N 2 -dG adduct ( Figure I). In vitro primer extension studies using purified high-fidelity DNA polymerases have revealed that this lesion stalls the progress of high-fidelity DNA polymerases, although small amounts of bypass have been observed [24,36,74,[78][79][80]. By contrast, although the rates of DNA replication catalyzed by Dpo4 are markedly retarded, translesion bypass by Dpo4 is much more facile than by BF, where polymerase blockage predominates [36] (L. Oum, PhD thesis, New York University, 2007).…”

Section: Box 3 Benzo[a]pyrene-derived Dna Lesionsmentioning

confidence: 99%

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Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Broyde¹,

Wang²,

Rechkoblit³

et al. 2008

Trends in Biochemical Sciences

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When a high-fidelity DNA polymerase encounters certain DNA-damage sites, its progress can be stalled and one or more lesion-bypass polymerases are recruited to transit the lesion. Here, we consider two representative types of lesions: (i) 7,8-dihydro-8-oxogua-nine (8-oxoG), a small, highly prevalent lesion caused by oxidative damage; and (ii) bulky lesions derived from the environmental pre-carcinogen benzo [a]pyrene, in the high-fidelity DNA polymerase Bacillus fragment (BF) from Bacillus stearothermophilus and in the lesion-bypass DNA polymerase IV (Dpo4) from Sulfolobus solfataricus. The tight fit of the BF polymerase around the nascent base pair contrasts with the more spacious, solvent-exposed active site of Dpo4, and these differences in architecture result in distinctions in their respective functions: one-step versus stepwise polymerase translocation, mutagenic versus accurate bypass of 8-oxoG, and polymerase stalling versus mutagenic bypass at bulky benzo[a]pyrene-derived lesions. Lesions and DNA polymerasesUntil 1999, it was widely understood that bacteria have three DNA polymerases and mammals have five [1]. In 1999, however, an entirely new category of polymerases was discovered in prokaryotes and eukaryotes [2-4] -the lesion-bypass DNA polymerases. The function of lesion-bypass polymerases is to replicate past lesion-containing DNA templates in a process called translesion synthesis [5][6][7]. Now at least 16 DNA polymerases are known in eukaryotes [8] and five in bacteria [9]. Furthermore, since 1999, crystal structures of DNA polymerases, including those containing lesions, have provided new structural insights into the mechanistic aspects of translesion synthesis and polymerase stalling associated with DNA lesions. For a review of the structures and mechanisms of DNA polymerases up to the year 2005, see Ref.[10].Here, we discuss the structural and functional features of representative high-fidelity and lesion-bypass DNA polymerases (Box 1) and how these features affect the processing of certain forms of DNA damage. The lesions considered are derived from reactions of intermediates produced by endogenous sources or from the metabolic activation of environmental genotoxic

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Section: Box 3 Benzo[a]pyrene-derived Dna Lesionsmentioning

confidence: 99%

Section: Box 3 Benzo[a]pyrene-derived Dna Lesionsmentioning

confidence: 99%

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Broyde¹,

Wang²,

Rechkoblit³

et al. 2008

Trends in Biochemical Sciences

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“…It is metabolized in vivo to an ultimate carcinogen, anti-benzo [a]pyrene diol epoxide (BPDE), which may bind to an exocylic amine group at N 2 -deoxyguanosine (dG) or N 6 -deoxyadenosine(dA) in DNA [8]. It is possible to form four stereoisomers of anti-BPDE-N 2 dG and four stereoisomers of anti-BPDE-N 6 dA, derived from the reaction of (±)-anti-BPDE with DNA [9]. However, the amount of BPDE-N 6 dA adducts formed in lung cells are 2 orders of magnitude lower than that of the anti-BPDE-N 2 dG adducts [10].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, it is more important to develop a fast and sensitive analytical method specifically for detection of the four stereoisomers of anti-BPDE-N 2 dG. The in vivo activation, detoxification, and elim-ination of benzo(a)pyrene, formation of DNA adducts and followed enzyme processing all display stereoselectivity at certain degree [9,11]. The metabolic intermediates of benzo[a]pyrene, 7,8-epoxide and trans -7,8-diol, as well as the two stereoisomeric diol epoxides (syn-and anti-BPDE) are all optically active.…”

Section: Introductionmentioning

confidence: 99%

Ultra-performance liquid chromatography–tandem mass spectrometry for rapid and highly sensitive analysis of stereoisomers of benzo[a]pyrene diol epoxide–DNA adducts

Feng

Wang

Huang

et al. 2009

Journal of Chromatography B

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“…[13][14][15][16] NMR solution studies of bulky carcinogen-DNA adducts have provided considerable insights into adduct conformations. 17,18 An intriguing finding is the importance of base sequence context in governing the conformations of such DNA adducts. Indeed, equilibria between different adduct conformations can be governed by the sequences of adjacent base pairs, and even next nearest neighbors can influence the balance of populations in different conformers.…”

Section: Introductionmentioning

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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NMR Solution Structures of Stereoisomeric Covalent Polycyclic Aromatic Carcinogen−DNA Adducts: Principles, Patterns, and Diversity

Cited by 331 publications

References 145 publications

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Ultra-performance liquid chromatography–tandem mass spectrometry for rapid and highly sensitive analysis of stereoisomers of benzo[a]pyrene diol epoxide–DNA adducts

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

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