Cytotoxic and mutagenic properties of alkyl phosphotriester lesions in Escherichia coli cells

Wu, Jiabin; Wang, Pengcheng; Wang, Yinsheng

doi:10.1093/nar/gky140

Cited by 16 publications

(39 citation statements)

References 33 publications

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“…In addition to methyl base adducts, some methylating agents also react with the DNA phosphate backbone to form methyl DNA phosphate adducts—B 1 pMeB 2 (Figure 2, see details in Section 3.1). B 1 pMeB 2 adducts were demonstrated to induce TT→GT and TT→GC mutations [71], inhibit RNA synthesis [72], and affect the binding affinity of DNA to other macromolecules [73].…”

Section: Smoking-related Dna Adducts In Humansmentioning

confidence: 99%

Recent Studies on DNA Adducts Resulting from Human Exposure to Tobacco Smoke

Stepanov

Hecht

2019

Toxics

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DNA adducts are believed to play a central role in the induction of cancer in cigarette smokers and are proposed as being potential biomarkers of cancer risk. We have summarized research conducted since 2012 on DNA adduct formation in smokers. A variety of DNA adducts derived from various classes of carcinogens, including aromatic amines, polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, alkylating agents, aldehydes, volatile carcinogens, as well as oxidative damage have been reported. The results are discussed with particular attention to the analytical methods used in those studies. Mass spectrometry-based methods that have higher selectivity and specificity compared to 32P-postlabeling or immunochemical approaches are preferred. Multiple DNA adducts specific to tobacco constituents have also been characterized for the first time in vitro or detected in vivo since 2012, and descriptions of those adducts are included. We also discuss common issues related to measuring DNA adducts in humans, including the development and validation of analytical methods and prevention of artifact formation.

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Section: Smoking-related Dna Adducts In Humansmentioning

confidence: 99%

Recent Studies on DNA Adducts Resulting from Human Exposure to Tobacco Smoke

Stepanov

Hecht

2019

Toxics

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“…5-Hydroxymethyluracil (5hmU) blocks replication by 20%, but it is not mutagenic in human cells [60]. The S p alkyl phosphotriester ( S p -alkyl-PTE) lesions display comparable replication bypass efficiency to unmodified DNA in E. coli ; S p -Me-PTE is mutagenic causing TT>GT (50%) and TT>GC (15%) mutations [61]. In contrast, R p -alkyl-PTEs block DNA replication (30–70%) but are not mutagenic [61].…”

Section: Discussion On Individual Modificationsmentioning

confidence: 99%

“…The S p alkyl phosphotriester ( S p -alkyl-PTE) lesions display comparable replication bypass efficiency to unmodified DNA in E. coli ; S p -Me-PTE is mutagenic causing TT>GT (50%) and TT>GC (15%) mutations [61]. In contrast, R p -alkyl-PTEs block DNA replication (30–70%) but are not mutagenic [61]. Interestingly, n Pr- and n Bu-PTEs exhibit higher bypass efficiencies than Me- and Et-PTEs [61].…”

Section: Discussion On Individual Modificationsmentioning

confidence: 99%

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Biological Evaluation of DNA Biomarkers in a Chemically Defined and Site-Specific Manner

Bian

Delaney

Zhou

et al. 2019

Toxics

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As described elsewhere in this Special Issue on biomarkers, much progress has been made in the detection of modified DNA within organisms at endogenous and exogenous levels of exposure to chemical species, including putative carcinogens and chemotherapeutic agents. Advances in the detection of damaged or unnatural bases have been able to provide correlations to support or refute hypotheses between the level of exposure to oxidative, alkylative, and other stresses, and the resulting DNA damage (lesion formation). However, such stresses can form a plethora of modified nucleobases, and it is therefore difficult to determine the individual contribution of a particular modification to alter a cell’s genetic fate, as measured in the form of toxicity by stalled replication past the damage, by subsequent mutation, and by lesion repair. Chemical incorporation of a modification at a specific site within a vector (site-specific mutagenesis) has been a useful tool to deconvolute what types of damage quantified in biologically relevant systems may lead to toxicity and/or mutagenicity, thereby allowing researchers to focus on the most relevant biomarkers that may impact human health. Here, we will review a sampling of the DNA modifications that have been studied by shuttle vector techniques.

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“…19–21 One recent study suggested that the bacterial O 6 -alkylguanine transferase Ada was required for the TT to GT or GC mutations induced by the methyl DNA phosphate adduct lesion. 22 Previous studies from our laboratory have shown that NNK-derived electrophilic diazonium ions 10 – 12 (Scheme 1) react with the nonbridging oxygens of the DNA internucleotide phosphate moiety. 23–25 Both POB and PHB phosphate adducts were quantified in rat tissues at relatively high levels.…”

Section: Introductionmentioning

confidence: 99%

Mass Spectrometric Quantitation of Pyridyloxobutyl DNA Phosphate Adducts in Rats Chronically Treated with N′-Nitrosonornicotine

Cao

et al. 2019

Chem. Res. Toxicol.

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The tobacco-specific carcinogens N´-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) require metabolic activation to exert their carcinogenicity. NNN and NNK are metabolized to the same reactive diazonium ions, which alkylate DNA forming pyridyloxobutyl (POB) DNA base and phosphate adducts. We have characterized the formation of both POB DNA base and phosphate adducts in NNK-treated rats, and the formation of POB DNA base adducts in NNN-treated rats. However, POB DNA phosphate adducts in NNN-treated rats are still uncharacterized. In this study, we quantified the levels of POB DNA phosphate adducts in tissues of rats chronically treated with (S)-NNN or (R)-NNN for 10, 30, 50, and 70 weeks during a carcinogenicity study. The highest amounts of POB DNA phosphate adducts were observed in the esophagus of the (S)-NNN-treated rats, with a maximum level of 5400 ± 317 fmol/mg DNA at 50 weeks. The abundance of POB DNA phosphate adducts in the esophagus was consistent with the results of the carcinogenicity study showing that the esophagus was the primary site of tumor formation from treatment with (S)-NNN. Compared to the (R)-NNN group, the levels of POB DNA phosphate adducts were higher in the oral mucosa, esophagus and liver, while lower in the nasal mucosa of the (S)-NNN-treated rats. Among ten combinations of all isomers of POB DNA phosphate adducts, Ap(POB)C and combinations with thymidine predominated across all the rat tissues examined. In the primary target tissue, esophageal mucosa, Ap(POB)C accounted for ~20% of total phosphate adducts in the (S)-NNN treatment group throughout the 70 weeks, with levels ranging from 780 ± 194 to 1010 ± 700 fmol/mg DNA. The results of this study showed that POB DNA phosphate adducts were present in high levels and persisted in target tissues of rats chronically treated with (S)- or (R)-NNN. These results improve our understanding of DNA damage during NNN-induced carcinogenesis. The predominant POB DNA phosphate isomers observed, such as Ap(POB)C, may serve as biomarkers for monitoring chronic exposure of tobacco-specific nitrosamines in humans.

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Cytotoxic and mutagenic properties of alkyl phosphotriester lesions in Escherichia coli cells

Cited by 16 publications

References 33 publications

Recent Studies on DNA Adducts Resulting from Human Exposure to Tobacco Smoke

Recent Studies on DNA Adducts Resulting from Human Exposure to Tobacco Smoke

Biological Evaluation of DNA Biomarkers in a Chemically Defined and Site-Specific Manner

Mass Spectrometric Quantitation of Pyridyloxobutyl DNA Phosphate Adducts in Rats Chronically Treated with N′-Nitrosonornicotine

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