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• W2048184132 startingPage "1730" @default.
• W2048184132 abstract "Causal links exist between smoking cigarettes and cancer development. Some genotoxic agents in cigarette smoke are capable of alkylating nucleobases in DNA, and higher levels of ethylated DNA lesions were observed in smokers than in nonsmokers. In this study, we examined comprehensively how the regioisomeric O2-, N3-, and O4-ethylthymidine (O2-, N3-, and O4-EtdT, respectively) perturb DNA replication mediated by purified human DNA polymerases (hPols) η, κ, and ι, yeast DNA polymerase ζ (yPol ζ), and the exonuclease-free Klenow fragment (Kf–) of Escherichia coli DNA polymerase I. Our results showed that hPol η and Kf– could bypass all three lesions and generate full-length replication products, whereas hPol ι stalled after inserting a single nucleotide opposite the lesions. Bypass conducted by hPol κ and yPol ζ differed markedly among the three lesions. Consistent with its known ability to efficiently bypass the minor groove N2-substituted 2′-deoxyguanosine lesions, hPol κ was able to bypass O2-EtdT, though it experienced great difficulty in bypassing N3-EtdT and O4-EtdT. yPol ζ was only modestly blocked by O4-EtdT, but the polymerase was strongly hindered by O2-EtdT and N3-EtdT. LC–MS/MS analysis of the replication products revealed that DNA synthesis opposite O4-EtdT was highly error-prone, with dGMP being preferentially inserted, while the presence of O2-EtdT and N3-EtdT in template DNA directed substantial frequencies of misincorporation of dGMP and, for hPol ι and Kf–, dTMP. Thus, our results suggested that O2-EtdT and N3-EtdT may also contribute to the AT → TA and AT → GC mutations observed in cells and tissues of animals exposed to ethylating agents." @default.
• W2048184132 created "2016-06-24" @default.
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• W2048184132 date "2013-11-01" @default.
• W2048184132 modified "2023-09-23" @default.
• W2048184132 title "Replication across Regioisomeric Ethylated Thymidine Lesions by Purified DNA Polymerases" @default.
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• W2048184132 doi "https://doi.org/10.1021/tx4002995" @default.
• W2048184132 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3863382" @default.
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