Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Meneni, Srinivasarao; Liang, Fengting; Cho, Bongsup P.

doi:10.1016/j.jmb.2006.12.023

Cited by 24 publications

(90 citation statements)

References 68 publications

(145 reference statements)

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“…The utility of fluorine tagged aromatic amine DNA adducts as an effective structure probe has well been documented. 15, 27, 28, 44 The modified template was annealed with various primers to create four model duplexes: full duplex (16/16-mer), −3 deletion (16/13-mer), −2 deletion (16/14-mer) and −1 deletion (16/15-mer)(Fig. 1c).…”

Section: Resultsmentioning

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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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%

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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“…The single guanines in these model sequences were adducted with fluoroaminofluorene adduct (dG-FAF). The utility of fluorine-tagged aromatic amine carcinogens as an effective conformational probe has been well documented (10,35,36). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2A, trace a). We have accumulated an extensive collection of 19 F NMR data with FAF-modified duplexes in various sequence settings and found that in all cases that the S-type conformer fluorine is always shielded (upfield) relative to that of the external binding B-type conformer (35,37). 19 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).…”

Section: Resultsmentioning

confidence: 99%

“…have shown previously (12,32,33,35,39) that purine bases 3Ј to the FAF-adducted site favors the S-conformation, whereas the presence of pyrimidine bases 5Ј to the lesion site favored the major groove B-conformer (36). In full duplexes, a 5Ј-T favors a higher percentage of the major groove B-type conformer, whereas a 5Ј-C favors the stacked conformation.…”

Section: F Nmr Studies Of Binary and Ternary Complexes-wementioning

confidence: 88%

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Insights into the Conformation of Aminofluorene-Deoxyguanine Adduct in a DNA Polymerase Active Site

Vaidyanathan

Liang

Beard

et al. 2013

Journal of Biological Chemistry

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Background: DNA lesions in different sequence contexts exhibit alternate conformations. Results: DNA adduct conformation is differentially modulated by DNA structure, DNA polymerase, and the presence of an incoming nucleoside triphosphate. Conclusion: Adduct conformation is influenced by binding of a non-hydrolysable nucleotide to pol ␤ but not Klenow fragment. Significance: Adduct conformation and coding potential is modulated by constraints imposed by the polymerase active site.

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“…The available lesion-containing crystal structures provide a springboard for molecular modeling and dynamics studies for cases in which crystals are not yet available [36,37,44,45]. Eagerly awaited are future structural and biochemical studies of lesion-containing DNA polymerases, to provide further insights into mechanisms of high-and low-fidelity translesion bypass.…”

Section: Concluding Remarks and Future Perspectivesmentioning

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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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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Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Cited by 24 publications

References 68 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

Insights into the Conformation of Aminofluorene-Deoxyguanine Adduct in a DNA Polymerase Active Site

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

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