Efficient nonmutagenic replication bypass of DNAs containing β‐adducts of styrene oxide at adenine N<sup>6</sup>

Kanuri, Manorama; Finneman, Jari I.; Harris, Constance M.; Harris, Thomas M.; Lloyd, R. Stephen

doi:10.1002/em.10030

Cited by 11 publications

(21 citation statements)

References 24 publications

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“…HPLC-ESI – -MS/MS sequencing of primer extension products confirmed that replication past N 6 -HB-dA I was largely error free (Schemes and ). These results are consistent with previous studies for structurally analogous adducts such as N 6 -HB-dA II, N 6 -THB-dA, and N 6 -dA adducts of styrene oxide. , Additionally, hpols η, ι, and κ, Pol T7, and Dpo4 were able to bypass the N 6 -THB-dA adduct in an efficient and error-free manner …”

Section: Discussionsupporting

confidence: 92%

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Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Kotapati

Wickramaratne

Esades

et al. 2015

Chem. Res. Toxicol.

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N 6-(2-Hydroxy-3-buten-1-yl)-2′-deoxyadenosine (N6-HB-dA I) and N6,N6-(2,3-dihydroxybutan-1,4-diyl)-2′-deoxyadenosine (N6,N6-DHB-dA) are exocyclic DNA adducts formed upon alkylation of the N6 position of adenine in DNA by epoxide metabolites of 1,3-butadiene (BD), a common industrial and environmental chemical classified as a human and animal carcinogen. Since the N6-H atom of adenine is required for Watson-Crick hydrogen bonding with thymine, N6-alkylation can prevent adenine from normal pairing with thymine, potentially compromising the accuracy of DNA replication. To evaluate the ability of BD-derived N6-alkyladenine lesions to induce mutations, synthetic oligodeoxynucleotides containing site-specific (S)-N6-HB-dA I and (R,R)-N6,N6-DHB-dA adducts were subjected to in vitro translesion synthesis in the presence of human DNA polymerases β, η, ι, and κ. While (S)-N6-HB-dA I was readily bypassed by all four enzymes, only polymerases η and κ were able to carry out DNA synthesis past (R,R)-N6,N6-DHB-dA. Steady-state kinetic analyses indicated that all four DNA polymerases preferentially incorporated the correct base (T) opposite (S)-N6-HB-dA I. In contrast, hPol β was completely blocked by (R,R)-N6,N6-DHB-dA, while hPol η and κ inserted A, G, C, or T opposite the adduct with similar frequency. HPLC-ESI-MS/MS analysis of primer extension products confirmed that while translesion synthesis past (S)-N6-HB-dA I was mostly error-free, replication of DNA containing (R,R)-N6,N6-DHB-dA induced significant numbers of A, C, and G insertions and small deletions. These results indicate that singly substituted (S)-N6-HB-dA I lesions are not miscoding, but exocyclic (R,R)-N6,N6-DHB-dA adducts are strongly mispairing, probably due to their inability to form stable Watson-Crick pairs with dT.

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Section: Discussionsupporting

confidence: 92%

“…These results are consistent with previous studies for structurally analogous adducts such as N 6 -HB-dA II, N 6 -THB-dA, and N 6 -dA adducts of styrene oxide. 43,59 Additionally, hpols η , ι , and κ , Pol T7, and Dpo4 were able to bypass N 6 -THB-dA adduct in an efficient and error-free manner. 57 …”

Section: Discussionmentioning

confidence: 99%

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Kotapati

Wickramaratne

Esades

et al. 2015

Chem. Res. Toxicol.

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“…Several examples in the literature indicate that certain types of DNA adducts have a higher probability of causing cell death rather than mutations (Beland & Kadlubar, 1990;Casciano, 2000). Likewise, studies with specific chemicals and their stereoisomers have shown that, although a reactive metabolite may adduct to a specific base, the biological response is dependent on the chirality of the adduct and the local DNA sequence context (Latham et al, 1993;Moriya et al, 1996;Kanuri et al, 2001).…”

Section: Mutagenic Efficiencymentioning

confidence: 96%

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

Jarabek

Pottenger

Andrews

et al. 2009

Critical Reviews in Toxicology

115

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The assessment of human cancer risk from chemical exposure requires the integration of diverse types of data. Such data involve effects at the cell and tissue levels. This report focuses on the specific utility of one type of data, namely DNA adducts. Emphasis is placed on the appreciation that such DNA adduct data cannot be used in isolation in the risk assessment process but must be used in an integrated fashion with other information. As emerging technologies provide even more sensitive quantitative measurements of DNA adducts, integration that establishes links between DNA adducts and accepted outcome measures becomes critical for risk assessment. The present report proposes an organizational approach for the assessment of DNA adduct data (e.g., type of adduct, frequency, persistence, type of repair process) in concert with other relevant data, such as dosimetry, toxicity, mutagenicity, genotoxicity, and tumor incidence, to inform characterization of the mode of action. DNA adducts are considered biomarkers of exposure, whereas gene mutations and chromosomal alterations are often biomarkers of early biological effects and also can be bioindicators of the carcinogenic process.

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“…This is an incorrect assumption; the mutagenicity of each base is influenced by the base itself, its flanking bases, the potential for repair of each lesion, and the DNA strand that is affected [Latham et al, 1993;Moriya et al, 1996;Kanuri et al, 2001]. The assumption that each base is equally mutable is also not supported by their subsequent analysis, which shows widely differing dinucleotide spontaneous frequencies [Ross and Leavitt, 2010; Table II).…”

Section: Rdm Analysis Of the Mutation Spectra Is Based On Faulty Unsmentioning

confidence: 92%

Re‐evaluation of the big blue® mouse assay of propiconazole suggests lack of mutagenicity

Shane¹,

Zeiger²,

Piegorsch

et al. 2011

Environ and Mol Mutagen

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Propiconazole (PPZ) is a conazole fungicide that is not mutagenic, clastogenic, or DNA damaging in standard in vitro and in vivo genetic toxicity tests for gene mutations, chromosome aberrations, DNA damage, and cell transformation. However, it was demonstrated to be a male mouse liver carcinogen when administered in food for 24 months only at a concentration of 2,500 ppm that exceeded the maximum tolerated dose based on increased mortality, decreased body weight gain, and the presence of liver necrosis. PPZ was subsequently tested for mutagenicity in the Big Blue® transgenic mouse assay at the 2,500 ppm dose, and the result was reported as positive by Ross et al. ([2009]: Mutagenesis 24:149-152). Subsets of the mutants from the control and PPZ-exposed groups were sequenced to determine the mutation spectra and a multivariate clustering analysis method purportedly substantiated the increase in mutant frequency with PPZ (Ross and Leavitt. [2010]: Mutagenesis 25:231-234). However, as reported here, the results of the analysis of the mutation spectra using a conventional method indicated no treatment-related differences in the spectra. In this article, we re-examine the Big Blue® mouse findings with PPZ and conclude that the compound does not act as a mutagen in vivo.

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Efficient nonmutagenic replication bypass of DNAs containing β‐adducts of styrene oxide at adenine N⁶

Cited by 11 publications

References 24 publications

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

Re‐evaluation of the big blue® mouse assay of propiconazole suggests lack of mutagenicity

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Efficient nonmutagenic replication bypass of DNAs containing β‐adducts of styrene oxide at adenine N6

Cited by 11 publications

References 24 publications

Polymerase Bypass of N6-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Polymerase Bypass of N6-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

Re‐evaluation of the big blue® mouse assay of propiconazole suggests lack of mutagenicity

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Efficient nonmutagenic replication bypass of DNAs containing β‐adducts of styrene oxide at adenine N⁶

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene

Polymerase Bypass of N⁶-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene