Miscoding properties of 1,N6-ethanoadenine, a DNA adduct derived from reaction with the antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea

Hang, Bo; Chenna, Ahmed; Guliaev, Anton B.; B, Singer

doi:10.1016/j.mrfmmm.2003.07.006

Cited by 28 publications

(22 citation statements)

References 49 publications

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“…Compared with pol and pol , the higher activity of pol copying past N 2 ,3-⑀G observed here is similar to that seen previously for other etheno adducts, i.e. 1,N 2 -⑀G (29), 1,N 6 -⑀A (26,49), and 3,N 4 -⑀C (50). With regard to DNA polymerases, the extension pattern is particularly similar to that of bypass of 1,N 2 -⑀G; i.e.…”

Section: Table 2 Summary Of Pol Extension Products From Lc-ms/ms Analsupporting

confidence: 90%

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases

Zhao

Pence

Christov

et al. 2012

Journal of Biological Chemistry

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N2,3-Ethenoguanine (N2,3-ϵG) is one of the exocyclic DNA adducts produced by endogenous processes (e.g. lipid peroxidation) and exposure to bioactivated vinyl monomers such as vinyl chloride, which is a known human carcinogen. Existing studies exploring the miscoding potential of this lesion are quite indirect because of the lability of the glycosidic bond. We utilized a 2′-fluoro isostere approach to stabilize this lesion and synthesized oligonucleotides containing 2′-fluoro-N2,3-ϵ-2′-deoxyarabinoguanosine to investigate the miscoding potential of N2,3-ϵG by Y-family human DNA polymerases (pols). In primer extension assays, pol η and pol κ replicated through N2,3-ϵG, whereas pol ι and REV1 yielded only 1-base incorporation. Steady-state kinetics revealed that dCTP incorporation is preferred opposite N2,3-ϵG with relative efficiencies in the order of pol κ > REV1 > pol η ≈ pol ι, and dTTP misincorporation is the major miscoding event by all four Y-family human DNA pols. Pol ι had the highest dTTP misincorporation frequency (0.71) followed by pol η (0.63). REV1 misincorporated dTTP and dGTP with much lower frequencies. Crystal structures of pol ι with N2,3-ϵG paired to dCTP and dTTP revealed Hoogsteen-like base pairing mechanisms. Two hydrogen bonds were observed in the N2,3-ϵG:dCTP base pair, whereas only one appears to be present in the case of the N2,3-ϵG:dTTP pair. Base pairing mechanisms derived from the crystal structures explain the slightly favored dCTP insertion for pol ι in steady-state kinetic analysis. Taken together, these results provide a basis for the mutagenic potential of N2,3-ϵG.

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Section: Table 2 Summary Of Pol Extension Products From Lc-ms/ms Analsupporting

confidence: 90%

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases

Zhao

Pence

Christov

et al. 2012

Journal of Biological Chemistry

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“…The order of bypass efficiency, Pol T7 ~ Pol η > Dpo4 > Pol κ > Pol ι (Figure 1), is similar to the reported bypass efficiency past N 2 ,3-ethenoguanine by these polymerases. 32,42 Compared with Pol κ and Pol ι, Pol η exhibited higher bypass efficiency past the adducts 1, N 6 -ethenoadenine 43,44 and 1, N 6 -(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2´-deoxyadenosine (1, N 6 -γ-HMHP-dA) adduct (formed from DEB), 45 which has been proposed to contribute to mutagenicity of BD. 16 However, Pol ι showed some single base incorporation opposite 1, N 6 -γ-HMHP-dA, 45 and did not extend primer well opposite N 2 ,3-ethenoguanine.…”

Section: Discussionmentioning

confidence: 99%

Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N⁶-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases

Cho

Guengerich

2013

Chem. Res. Toxicol.

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1,2,3,4-Diepoxybutane (DEB), a metabolite of the carcinogen butadiene, has been shown to cause glutathione (GSH)-dependent base-substitution mutations, especially A:T to G:C in Salmonella typhimurium TA1535 (Chem. Res. Toxicol. 23, 1544 (2010)) and Escherichia coli TRG8 cells (Chem. Res. Toxicol. 25, 1522 (2012)). We previously identified S-[4-(N6-deoxyadenosinyl)-2,3-dihydroxybutyl]GSH (N6dA-(OH)2butyl-GSH) as a major adduct in the reaction of S-(2-hydroxy-3,4-epoxybutyl)glutathione (DEB-GSH conjugate) with nucleosides and calf thymus DNA and in vivo in livers of mice and rats treated with DEB (Chem. Res. Toxicol. 25, 706 (2012)). For investigation of the miscoding potential of the major DEB-GSH conjugate-derived DNA adduct (N6dA-(OH)2butyl-GSH) and the effect of GSH conjugation on replication of DEB, extension studies were performed in duplex DNA substrates containing the site specifically-incorporated N6dA-(OH)2butyl-GSH adduct, N6-(2,3,4-trihydroxybutyl)deoxyadenosine adduct (N6dA-butanetriol), or unmodified deoxyadenosine (dA) by human DNA polymerases (Pol) η, ι, and κ, bacteriophage polymerase T7, and Sulfolobus solfataricus polymerase Dpo4. Although dTTP incorporation was the most preferred addition opposite the N6dA-(OH)2butyl-GSH adduct, N6dA-butanetriol adduct, or unmodified dA by all polymerases, dCTP misincorporation frequency opposite N6dA-(OH)2butyl-GSH was significantly higher than that opposite the N6dA-butanetriol adduct or unmodified dA by Pol κ or Pol T7. LC-MS/MS analysis of full-length primer extension products confirmed that Pol κ or Pol T7 incorporated the incorrect base C opposite N6dA-(OH)2butyl-GSH lesion. These results indicate the relevance of GSH-containing adducts for the A:T to G:C mutations produced by DEB.

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“…Human Pol ι , a paralogue of Pol η , was blocked by ε dA with a very small amount of synthesis past ε dA, which results in insertion of dCMP and, to a much lesser extent, dTMP, opposite ε dA. 274 The mutagenic potential of ε dA was also investigated using a single-stranded shuttle vector system in E. coli and in COS7 simian kidney cells. A nonmutagenic dTMP incorporation opposite ε dA was found as the nearly exclusive event in E. coli ; the lesion is, however, highly mutagenic in COS7 cells, which leads to a very high frequency of A → G transition (63%), followed by A → T (6%) and A → C (1%) transversions.…”

Section: Repair and Biological Consequences Of Oxidative Stress-inmentioning

confidence: 99%

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Cui

Niedernhofer

et al. 2016

Chem. Res. Toxicol.

150

135

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A variety of endogenous and exogenous agents can induce DNA damage and lead to genomic instability. Reactive oxygen species (ROS), an important class of DNA damaging agents, are constantly generated in cells as a consequence of endogenous metabolism, infection/inflammation, and/or exposure to environmental toxicants. A wide array of DNA lesions can be induced by ROS directly, including single-nucleobase lesions, tandem lesions, and hypochlorous acid (HOCl)/hypobromous acid (HOBr)-derived DNA adducts. ROS can also lead to lipid peroxidation, whose byproducts can also react with DNA to produce exocyclic DNA lesions. A combination of bioanalytical chemistry, synthetic organic chemistry, and molecular biology approaches have provided significant insights into the occurrence, repair, and biological consequences of oxidatively induced DNA lesions. The involvement of these lesions in the etiology of human diseases and aging was also investigated in the past several decades, suggesting that the oxidatively induced DNA adducts, especially bulky DNA lesions, may serve as biomarkers for exploring the role of oxidative stress in human diseases. The continuing development and improvement of LC-MS/MS coupled with the stable isotope-dilution method for DNA adduct quantification will further promote research about the clinical implications and diagnostic applications of oxidatively induced DNA adducts.

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Miscoding properties of 1,N6-ethanoadenine, a DNA adduct derived from reaction with the antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea

Cited by 28 publications

References 49 publications

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases

Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N⁶-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

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Miscoding properties of 1,N6-ethanoadenine, a DNA adduct derived from reaction with the antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea

Cited by 28 publications

References 49 publications

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases

Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N6-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

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Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N⁶-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases