Structure–Function Characteristics of Aromatic Amine‐DNA Adducts

Cho, Bongsup

doi:10.1002/9783527630110.ch10

Cited by 32 publications

(99 citation statements)

References 90 publications

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“…We have also accumulated an extensive collection of 19 F NMR spectra of fluorinated aminofluorene-modified duplexes in various sequence settings and found that in the base-displaced stacked (S) conformer fluorine is always shielded (upfield) relative to that of the external binding B-type conformer. 14, 15, 26, 29, 44, 48, 4919 F shielding is a hallmark for the van der Waals interaction and the ring current effect caused by the carcinogen moiety within the stacked and bulge duplexes (S-type conformation). 44 We have used a similar strategy to assign the signals in the 19 F NMR spectra of deletion duplexes, i.e., the signals (~ −115 ppm) near the coalescence temperatures arise from denatured single stranded modified exposed fluorine and non-stacked external B-type conformers, and shielded signals arise from a buried fluorinated carcinogen with excess van der Waals interactions with neighboring base pairs as occurs in S-type conformations.…”

Section: Resultsmentioning

confidence: 99%

“…2, 3 This effect may be due to its flexibility to accommodate both syn -stacked (S) and anti - (B-type) glycosidic conformations. 14–19 On the other hand, the bulky N -acetylated dG-AAF lesion exists primarily in the highly distorting syn -glycosidic stacked (S)- or wedge (W)-conformations and strongly blocks the polymerase, thus resulting in frameshift mutations. 16–18, 20 In mammalian cells, however, the two lesions mostly result in point mutations.…”

Section: Introductionmentioning

confidence: 99%

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Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Sandineni

Lin

MacKerell

et al. 2013

Chem. Res. Toxicol.

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2-Acetylaminofluorene (AAF) is a prototype arylamine carcinogen that forms C8-substituted dG-AAF and dG-AF as the major DNA lesions. The bulky N-acetylated dG-AAF lesion can induce various frameshift mutations depending on the base sequence around the lesion. We hypothesized that the thermodynamic stability of bulged-out slipped mutagenic intermediates (SMIs) is directly related to deletion mutations. The objective of the present study was to probe the structural/conformational basis of various dG-AAF–induced SMIs formed during a translesion synthesis. We performed spectroscopic, thermodynamic, and molecular dynamics studies of several AAF-modified 16-mer model DNA duplexes, including fully paired and −1, −2, and −3 deletion duplexes of the 5′-CTCTCGATG[FAAF]CCATCAC-3′ sequence and an additional −1 deletion duplex of the 5′-CTCTCGGCG[FAAF]CCATCAC-3′ NarI sequence. Modified deletion duplexes existed in a mixture of external B and stacked S conformers, with the population of the S conformer being ‘GC’ −1 (73%) > ‘AT’ −1 (72%) > full (60%) > −2 (55%) > −3 (37%). Thermodynamic stability was in the order of −1 deletion > −2 deletion > fully paired > −3 deletion duplexes. These results indicate that the stacked S-type conformer of SMIs are thermodynamically more stable than the conformationally flexible external B conformer. Results from the molecular dynamics simulations indicate perturbation of base stacking dominate the relative stability along with contributions from bending, duplex dynamics, solvation effects that are important in specific cases. Taken together, these results support a hypothesis that the conformational and thermodynamic stabilities of the SMIs are critical determinants for the induction of frameshift mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Sandineni

Lin

MacKerell

et al. 2013

Chem. Res. Toxicol.

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“…12,36 This linkage restricts the twisting between the two aromatic rings that is possible in FABP, thus enhancing the stacking surface (Figure 1A,B). 10,30,37 This simple topological difference is fascinating in its impact on the structural and biochemical properties of the lesion.…”

Section: Discussionmentioning

confidence: 99%

Conformational Insights into the Lesion and Sequence Effects for Arylamine-Induced Translesion DNA Synthesis: ¹⁹F NMR, Surface Plasmon Resonance, and Primer Kinetic Studies

et al. 2014

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Adduct-induced DNA damage can affect transcription efficiency and DNA replication and repair. We previously investigated the effects of the 3′-next flanking base (G*CT vs G*CA; G*, FABP, N-(2′-deoxyguanosin-8-yl)-4′-fluoro-4-aminobiphenyl; FAF, N-(2′-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene) on the conformation of arylamine-DNA lesions in relation to E. coli nucleotide excision repair (JainV.HiltonB.LinB.PatnaikS.LiangF.DarianE.ZouY.MackerellA. D.Jr.ChoB. P.JainV.HiltonB.LinB.PatnaikS.LiangF.DarianE.ZouY.MackerellA. D.Jr.ChoB. P.23180767Nucleic Acids Res.201341869880). Here, we report the differential effects of the same pair of sequences on DNA replication in vitro by the polymerases exofree Klenow fragment (Kf-exo–) and Dpo4. We obtained dynamic 19F NMR spectra for two 19-mer modified templates during primer elongation: G*CA [d(5′-CTTACCATCG*CAACCATTC-3′)] and G*CT [d(5′-CTTACCATCG*CTACCATTC-3′)]. We found that lesion stacking is favored in the G*CT sequence compared to the G*CA counterpart. Surface plasmon resonance binding results showed consistently weaker affinities for the modified DNA with the binding strength in the order of FABP > FAF and G*CA > G*CT. Primer extension was stalled at (n) and near (n – 1 and n + 1) the lesion site, and the extent of blockage and the extension rates across the lesion were influenced by not only the DNA sequences but also the nature of the adduct’s chemical structure (FAF vs FABP) and the polymerase employed (Kf-exo– vs Dpo4). Steady-state kinetics analysis with Kf-exo– revealed the most dramatic sequence and lesion effects at the lesion (n) and postinsertion (n + 1) sites, respectively. Taken together, these results provide insights into the important role of lesion-induced conformational heterogeneity in modulating translesion DNA synthesis.

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“…The NarI sequence is a hot-spot for frameshift mutations mediated by the N-linked C8-dG adduct of N-acetyl-2-aminofluorene (AAF) [19][20][21]. Within the NarI(12) duplex, the PhOdG lesion was shown to adopt the major groove B conformation opposite C, with minimal disruption to the duplex structure [23].…”

Section: Introductionmentioning

confidence: 99%

“…The phenolic C-linked C8-dG adducts belong to a larger class of C8-aryldG lesions produced by a number of chemical mutagens that include polycyclic aromatic hydrocarbons (PAHs) [15], estrogens [16], nitroaromatics [17] and arylhydrazines [18]. The phenolic O-linked C8-dG adducts are unique to phenol precursors, but are expected to be structurally similar to the corresponding nitrogen-linked C8-dG adducts produced by aromatic amine carcinogens [19][20][21]. For aromatic amines, structure-activity relationships have demonstrated that all of the potent carcinogens are polycyclic structures, while none of the single-ringed aniline derivatives are potent carcinogens [22].…”

Section: Introductionmentioning

confidence: 99%

Mutagenicity Analysis of C8-Phenoxy-Guanine in the NarI Recognition DNA Sequence

2014

J Toxins

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Phenoxyl radicals can covalently attach to the C8-site of 2′-deoxyguanosine (dG) to generate oxygen-linked biaryl ether C8-dG adducts. To determine the mutagenicity of an O-linked C8-dG adduct, C8-phenoxy-dG (PhOdG) was incorporated into the G 3 position (X) of the NarI recognition sequence within a 22-mer oligonucleotide template (5′-CTCGGCX-CCATCCCTTACGAGC, where X = dG, or PhOdG) using solid-phase DNA synthesis. The NarI (22) template was annealed to a 15-mer primer and in vitro mutagenicity was assessed using primer-extension assays with a high-fidelity replicative polymerase, Escherichia coli pol I Klenow fragment exo− (Kf − ), and a lesion-bypass Y-family polymerase, Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4). These studies predict that the O-linked C8-dG lesion PhOdG will have a low mutagenic effect, and is unlikely to contribute strongly to phenol toxicity.

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Structure–Function Characteristics of Aromatic Amine‐DNA Adducts

Cited by 32 publications

References 90 publications

Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Conformational Insights into the Lesion and Sequence Effects for Arylamine-Induced Translesion DNA Synthesis: ¹⁹F NMR, Surface Plasmon Resonance, and Primer Kinetic Studies

Mutagenicity Analysis of C8-Phenoxy-Guanine in the NarI Recognition DNA Sequence

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Structure–Function Characteristics of Aromatic Amine‐DNA Adducts

Cited by 32 publications

References 90 publications

Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Conformational Insights into the Lesion and Sequence Effects for Arylamine-Induced Translesion DNA Synthesis: 19F NMR, Surface Plasmon Resonance, and Primer Kinetic Studies

Mutagenicity Analysis of C8-Phenoxy-Guanine in the NarI Recognition DNA Sequence

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Conformational Insights into the Lesion and Sequence Effects for Arylamine-Induced Translesion DNA Synthesis: ¹⁹F NMR, Surface Plasmon Resonance, and Primer Kinetic Studies