Identification of N5-methyl-N5-formyl-2,5,6-triamino-4-hydroxypyrimidine as a major adduct in rat liver DNA after treatment with the carcinogens, N,N-dimethylnitrosamine or 1,2-dimethylhydrazine

Beranek, David T.; Weis, Constance C.; Evans, Frederick E.; Chetsanga, Christopher J.; Kadlubar, Fred F.

doi:10.1016/0006-291x(83)91195-6

Cited by 63 publications

(42 citation statements)

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“…Fapy-7-MeGua has been described in vivo, in the liver of rats treated with N,N-dimethylnitrosamine, or 1,2-dimethylhydrazine, and in rat bladder epithelial DNA after treatment with Nmethylnitrosourea (4,5). Furthermore opening of the imidazole ring of guanine yielding a non-methylated Fapy-Gua has been observed in animal (6) and in human tumor tissues (7).…”

Section: Introductionmentioning

confidence: 99%

Biological properties of imidazole ring-opened N7-methylguanine in M13mp18 phage DNA

1992

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Guanine residues methylated at the N-7 position (7-MeGua) are susceptible to cleavage of the imidazole ring yielding 2,6-diamino-4-hydroxy-5N-methylformamidopyrimidine (Fapy-7-MeGua). The presence of Fapy-7-MeGua in DNA template causes stops in DNA synthesis in vitro by E.coli DNA polymerase 1. The biological consequences of Fapy-7-MeGua lesions for survival and mutagenesis were investigated using single-stranded Ml 3mpl8 phage DNA. Fapy-7-MeGua lesions were generated in vitro in phage DNA by dimethylsulfate (DMS) methylation and subsequent ring opening of 7-MeGua by treatment with NaOH (DMSbase). The presence of Fapy-7-MeGua residues in Ml 3 phage DNA correlated with a significant decrease in transfection efficiency and an increase in mutation frequency in the lacZ gene, when transfected into SOSinduced JM1O5 E.coli cells. Sequencing analysis revealed unexpectedly, that mutation rate at guanine sites was only slightly increased, suggesting that Fapy-7-MeGua was not responsible for the overall increase in the mutagenic frequency of DMS-base treated DNA. In contrast, mutation frequency at adenine sites yielding A-G transitions was the most frequent event, 60-fold increased over DMS induced mutations. These results show that treatment with alkali of methylated single-stranded DNA generates a mutagenic adenine derivative, which mispairs with cytosine in SOS induced bacteria. The results also imply that the Fapy-7-MeGua in E.coli cells is primarily a lethal lesion.

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Section: Introductionmentioning

confidence: 99%

Biological properties of imidazole ring-opened N7-methylguanine in M13mp18 phage DNA

1992

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“…22, 23 Interestingly, imidazole ring opening of N7-alkyl-G adducts in RNA is 2–3 times faster than of their DNA counterparts, presumably due to the electron withdrawing effect of the 2′-hydroxyl group. 24 Aflatoxin B1 epoxide, 25–27 N -methylnitrosamines, 28–32 dimethyl sulfate, 33, 34 tobacco carcinogen 4-(methylnitrosamino)-1-(pyridyl)-1-butanone (NNK), 35 N-methylnitrosourea, 36 1, 2-dimethylhydrazine, N , N -dimethylnitrosamine, 28–32, 37 cyclophosphamide, 38, 39 mitomycin C, 40, 41 and ethyleneimine 42 are some examples of alkylating agents that give rise to N 5 substituted FAPy adducts. N 5 -substituted FAPy adducts are also induced by leinamycin, 20 pluramycins, 43 azinomycin, 44, 45 and S -(2-haloethyl)glutathione.…”

Section: Introductionmentioning

confidence: 99%

Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts

Pujari

Tretyakova

2016

Chem. Res. Toxicol.

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DNA nucleobases are the prime targets for chemical modifications by endogenous and exogenous electrophiles. Alkylation of the N7 position of guanine and adenine in DNA triggers base-catalyzed imidazole ring opening and the formation of N5-substituted formamidopyrimidine (N5-R-FAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B1 have been shown to persist in cells and to contribute to toxicity and mutagenicity. In contrast, the biological outcomes of other N5-substituted FAPy lesions have not been fully elucidated. To enable their structural and biological evaluation, N5-R-FAPy adducts must be site-specifically incorporated into synthetic DNA strands using phosphoramidite building blocks, which can be complicated by their unusual structural complexity. N5-R-FAPy exist as a mixture of rotamers and can undergo isomerization between α, β anomers and furanose-pyranose forms. In this Perspective, we will discuss the main types of N5-R-FAPy adducts and summarize the strategies for their synthesis and structural elucidation. We will also summarize the chemical biology studies conducted with N5-R-FAPy-containing DNA to elucidate their effects on DNA replication and to identify the mechanisms of N5-R-FAPy repair.

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“…MeFapy-dG has been characterized in vivo , in the liver of rats, 7, 8 and has also been observed in the urine of healthy humans. 9 In general, the MeFapy-dG adduct is considered non-miscoding, owing to the fact that the Watson-Crick face remains unaltered.…”

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confidence: 99%

Structural Basis for Error-Free Bypass of the 5-N-Methylformamidopyrimidine-dG Lesion by Human DNA Polymerase η and Sulfolobus solfataricus P2 Polymerase IV

et al. 2015

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2,6-Diamino-4-hydroxy-5N-methylformamidopyrimidine (MeFapy-dG) arises from N7-methylation of guanine followed by imidazole ring opening. The lesion has been reported to persist in animal tissues. Previous in vitro replication bypass investigations of the MeFapy-dG adduct revealed predominant insertion of C opposite the lesion, dependent on the identity of the DNA polymerase (Pol) and the local sequence context. Here we report crystal structures of ternary Pol•DNA•dNTP complexes between MeFapy-dG-adducted DNA template:primer duplexes and the Y-family polymerases human Pol η and P2 Pol IV (Dpo4) from Sulfolobus solfataricus. The structures of the hPol η and Dpo4 complexes at the insertion and extension stages, respectively, are representative of error-free replication, with MeFapydG in the anti conformation and forming Watson-Crick pairs with dCTP or dC.

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Identification of N5-methyl-N5-formyl-2,5,6-triamino-4-hydroxypyrimidine as a major adduct in rat liver DNA after treatment with the carcinogens, N,N-dimethylnitrosamine or 1,2-dimethylhydrazine

Cited by 63 publications

References 18 publications

Biological properties of imidazole ring-opened N7-methylguanine in M13mp18 phage DNA

Biological properties of imidazole ring-opened N7-methylguanine in M13mp18 phage DNA

Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts

Structural Basis for Error-Free Bypass of the 5-N-Methylformamidopyrimidine-dG Lesion by Human DNA Polymerase η and Sulfolobus solfataricus P2 Polymerase IV

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Identification of N5-methyl-N5-formyl-2,5,6-triamino-4-hydroxypyrimidine as a major adduct in rat liver DNA after treatment with the carcinogens, N,N-dimethylnitrosamine or 1,2-dimethylhydrazine

Cited by 63 publications

References 18 publications

Biological properties of imidazole ring-opened N7-methylguanine in M13mp18 phage DNA

Biological properties of imidazole ring-opened N7-methylguanine in M13mp18 phage DNA

Chemical Biology of N5-Substituted Formamidopyrimidine DNA Adducts

Structural Basis for Error-Free Bypass of the 5-N-Methylformamidopyrimidine-dG Lesion by Human DNA Polymerase η and Sulfolobus solfataricus P2 Polymerase IV

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Chemical Biology of N⁵-Substituted Formamidopyrimidine DNA Adducts