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, Na; Lin, Chong; Huang, Xiaoxia; Kolbanovskiy, Alexander; Hingerty, Brian E.; Amin, Shantu; Broyde, Suse; Geacintov, Nicholas E.; Patel, Dinshaw J.

doi:10.1016/j.jmb.2004.12.027

Cited by 57 publications

(45 citation statements)

References 62 publications

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“…Within these networks are genes involved in the organization and remodeling of chromatin, including MTA3, HDAC1, ATRX, MBD2, and MBD3 . These findings are in agreement with previous studies reporting that BaP can decrease global DNA methylation 136 , inhibit DNA methyltransferases in vitro 137 , and interfere with recruitment of the methylation machinery 138,139 . Although these studies have firmly established an epigenetic effect for BaP, their direct relevance to asthma remains debatable.…”

Section: Environmental Factors Exert Epigenetic Influences On Asthmasupporting

confidence: 93%

Environmental epigenetics of asthma: An update

2010

Journal of Allergy and Clinical Immunology

196

170

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Asthma, a chronic inflammatory disorder of the airway, is influenced by interplay between genetic and environmental factors now known to be mediated by epigenetics. Aberrant DNA methylation, altered histone modifications, specific microRNA expression, and other chromatin alterations orchestrate a complex early-life reprogramming of immune T cell response, dendritic cell function, macrophage activation, and a breach of airway epithelial barrier that dictates asthma risk and severity in later life. Adult-onset asthma is under analogous regulation. The sharp increase in asthma prevalence over the past two or three decades and the large variations among populations of similar racial/ethnic background but different environmental exposures favors a strong contribution of environmental factors. This review addresses the fundamental question of whether environmental influences on asthma risk, severity, and steroid resistance are partly due to differential epigenetic modulations. Current knowledge on epigenetic effects of tobacco smoke, microbial allergens, oxidants, airborne particulate matter, diesel exhaust particles, dietary methyl donors and other nutritional factors, and dust mites is discussed. Exciting findings have been generated by rapid technological advances and well-designed experimental and population studies. The discovery and validation of epigenetic biomarkers linked to exposure and/or asthma may lead to better epigenotyping of risk, prognosis, treatment prediction, and development of novel therapies.

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Section: Environmental Factors Exert Epigenetic Influences On Asthmasupporting

confidence: 93%

Environmental epigenetics of asthma: An update

2010

Journal of Allergy and Clinical Immunology

196

170

View full text Add to dashboard Cite

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“…Full exposure of the hydrocarbon rings and aromatic base G is extremely unfavorable in an aqueous environment. None of the experimentally observed DNA structures containing BP-dG adducts have shown such a fully exposed conformation (24)(25)(26)(27). The protein-free NMR structures have the BP ring system either intercalated or bound to DNA in the minor groove to avoid full exposure of the aromatic rings to water.…”

Section: Resultsmentioning

confidence: 99%

A structural gap in Dpo4 supports mutagenic bypass of a major benzo[ a ]pyrene dG adduct in DNA through template misalignment

Bauer

Xing²,

Yagi³

et al. 2007

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

139

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Erroneous replication of lesions in DNA by DNA polymerases leads to elevated mutagenesis. To understand the molecular basis of DNA damage-induced mutagenesis, we have determined the x-ray structures of the Y-family polymerase, Dpo4, in complex with a DNA substrate containing a bulky DNA lesion and incoming nucleotides. The DNA lesion is derived from an environmentally widespread carcinogenic polycyclic aromatic hydrocarbon, benzo[ a ]pyrene (BP). The potent carcinogen BP is metabolized to diol epoxides that form covalent adducts with cellular DNA. In the present study, the major BP diol epoxide adduct in DNA, BP- N 2 -deoxyguanosine (BP–dG), was placed at a template–primer junction. Three ternary complexes reveal replication blockage, extension past a mismatched lesion, and a −1 frameshift mutation. In the productive structures, the bulky adduct is flipped/looped out of the DNA helix into a structural gap between the little finger and core domains. Sequestering of the hydrophobic BP adduct in this new substrate-binding site permits the DNA to exhibit normal geometry for primer extension. Extrusion of the lesion by template misalignment allows the base 5′ to the adduct to serve as the template, resulting in a −1 frameshift. Subsequent strand realignment produces a mismatched base opposite the lesion. These structural observations, in combination with replication and mutagenesis data, suggest a model in which the additional substrate-binding site stabilizes the extrahelical nucleotide for lesion bypass and generation of base substitutions and −1 frameshift mutations.

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“…The chemical shifts of the aliphatic and aromatic BP ring protons are not sensitive to their interactions with the different sugar protons in the G6*G7 and G6G7* duplexes, which is also consistent with minor groove conformations (17,19) (Figure S5, Supplementary Data). Intercalative structures are characterized by significant upfield shifts of the BP aromatic ring protons due to base stacking interactions (36). …”

Section: Discussionmentioning

confidence: 99%

Exocyclic amino groups of flanking guanines govern sequence-dependent adduct conformations and local structural distortions for minor groove-aligned benzo[a]pyrenyl-guanine lesions in a GG mutation hotspot context

Rodríguez

Cai

Lin

et al. 2007

Nucleic Acids Research

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The environmental carcinogen benzo[a]pyrene (BP) is metabolized to reactive diol epoxides that bind to cellular DNA by predominantly forming N2-guanine adducts (G*). Mutation hotspots for these adducts are frequently found in 5′- ··· GG ··· dinucleotide sequences, but their origins are poorly understood. Here we used high resolution NMR and molecular dynamics simulations to investigate differences in G* adduct conformations in 5′- ··· CG*GC ··· and 5′- ··· CGG* C··· sequence contexts in otherwise identical 12-mer duplexes. The BP rings are positioned 5′ along the modified strand in the minor groove in both cases. However, subtle orientational differences cause strong distinctions in structural distortions of the DNA duplexes, because the exocyclic amino groups of flanking guanines on both strands compete for space with the BP rings in the minor groove, acting as guideposts for placement of the BP. In the 5′- ··· CGG* C ··· case, the 5′-flanking G · C base pair is severely untwisted, concomitant with a bend deduced from electrophoretic mobility. In the 5′- ··· CG*GC ··· context, there is no untwisting, but there is significant destabilization of the 5′-flanking Watson–Crick base pair. The minor groove width opens near the lesion in both cases, but more for 5′- ··· CGG*C···. Differential sequence-dependent removal rates of this lesion result and may contribute to the mutation hotspot phenomenon.

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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

Cited by 57 publications

References 62 publications

Environmental epigenetics of asthma: An update

Environmental epigenetics of asthma: An update

A structural gap in Dpo4 supports mutagenic bypass of a major benzo[ a ]pyrene dG adduct in DNA through template misalignment

Exocyclic amino groups of flanking guanines govern sequence-dependent adduct conformations and local structural distortions for minor groove-aligned benzo[a]pyrenyl-guanine lesions in a GG mutation hotspot context

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