Specific excision of methylation products from DNA of Escherichia coli treated with N-methyl-N'-nitro-N-nitrosoguanidine.
About: This article is published in Chemico-Biological Interactions.The article was published on 1970-08-01. It has received 146 citations till now. The article focuses on the topics: Methylation.
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TL;DR: This review complies DNAAlkylation data for both methylating and ethylating agents in a variety of systems and discusses the role these alkylation products plays in molecular mutagenesis.
Abstract: Alkylating agents, because of their ability to react directly with DNA either in vitro or in vivo, or following metabolic activation as in the case of the dialkylnitrosamines, have been used extensively in studying the mechanisms of mutagenicity and carcinogenicity. Their occurrence is widespread in the environment and human exposure from natural and pollutant sources is universal. Since most of these chemicals show varying degrees of both carcinogenicity and mutagenicity, and exhibit compound-specific binding patterns, they provide an excellent model for studying molecular dosimetry. Molecular dosimetry defines dose as the number of adducts bound per macromolecule and relates the binding of these adducts to the human mutagenic or carcinogenic response. This review complies DNA alkylation data for both methylating and ethylating agents in a variety of systems and discusses the role these alkylation products plays in molecular mutagenesis.
863 citations
TL;DR: This chapter discusses that since DNA is the carrier of genetic information and spontaneous mutations occur only at low frequency, cellular DNA has often been regarded as an essentially stable entity, but recent developments have necessitated a revision of this view.
Abstract: Publisher Summary This chapter discusses that since DNA is the carrier of genetic information and spontaneous mutations occur only at low frequency, cellular DNA has often been regarded as an essentially stable entity. Recent developments have necessitated a revision of this view. With the discovery of insertion elements, it became clear that certain segments of DNA can move between many different chromosomal sites. Further, the susceptibility of DNA to heat-induced degradation at moderate temperatures and neutral pH leads to hydrolytic decay at a much faster rate than that expected from spontaneous mutation frequencies. The latter, somewhat paradoxical, observation can be rationalized by postulating the existence of efficient repair mechanisms to maintain the integrity of DNA. The chapter also discusses that several enzymes that act specifically on hydrolytically-damaged nucleotide residues in DNA have recently been discovered, purified, and characterized, and they are the main subject of the present review. Some of these enzymes, the DNA glycosylases, belong to a previously unrecognized class of enzymes that cleave base–sugar bonds in DNA. In addition to their role in surveying and removing DNA damage that would otherwise lead to unacceptable spontaneous mutation frequencies, the same enzymes may also play an important role in the repair of cellular lesions introduced by ionizing radiation or by exposure to chemical mutagens such as alkylating agents, nitrous acid, or bisulfite.
526 citations
TL;DR: Further studies of mutation in picornaviruses or their RNAs would be fruitful since these viral RNAs are also messenger RNAs and are directly translated, whereas in vivo studies, definitive information is still lacking as to whether alkylation of DNA, RNA, or perhaps protein is the biologically important event.
Abstract: Publisher Summary This chapter discusses the studies relating to the chemical nature of alkylation, from the products of nucleoside alkylation to in vivo effects of alkylating agents that are oncogenic. The reactions of simple methylating agents with nucleosides, nucleotides, and polynucleotides have also been discussed in the chapter. More recent studies of the mechanism of alkylation by nitroso compounds and ethylating agents have shown that both qualitatively and quantitatively the site of alkylation is a function of both the type of reagent used and the conformation and milieu of the nucleic acid. However, translation of this body of knowledge to an understanding of the biological mechanism of alkylation-induced mutagenesis and carcinogenesis is difficult. Further studies of mutation in picornaviruses or their RNAs would be fruitful since these viral RNAs are also messenger RNAs and are directly translated, whereas in vivo studies, definitive information is still lacking as to whether alkylation of DNA, RNA, or perhaps protein, is the biologically important event.
409 citations
TL;DR: The production of the FPG protein in cells harboring the pFPG230 plasmid was 800-fold higher than that of the wild type strain after induction by isopropyl-beta-D-thio-galactopyranoside, suggesting that the F PG protein possesses a tightly bound metal ion.
331 citations
TL;DR: This chapter deals with the formation and metabolism of alkylated purines in nucleic acids and briefly discusses other alkylation reactions leading to the alkylphosphate triester production andAlkylated pyrimidines.
Abstract: Publisher Summary Alkylation of nucleic acids occurs both physiologically within living cells and after the administration of compounds that are either themselves direct chemical alkylating agents or are converted into alkylating agents by metabolic activation. Some of these compounds are highly potent carcinogens. Carcinogenicity of these agents is due to the alkylation of certain cellular components because no other degradation product nor is the compound itself oncogenic. This chapter deals with the formation and metabolism of alkylated purines in nucleic acids. It briefly discusses other alkylation reactions leading to the alkylphosphate triester production and alkylated pyrimidines. It also presents evidences favoring particular critical targets for the action of alkylating carcinogens. The attack on nucleic acids by carcinogenic alkylating agents is not entirely random and generally leads to the formation of alkylated nucleosides at many different sites distributed throughout the cellular nucleic acids. Carcinogenesis is not necessarily mediated through mutagenesis in somatic cells. However, it is observed that carcinogenic action could be mediated through a distinct action of the electrophilic reactant.
290 citations
References
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TL;DR: Genetic studies of alkylation mutants in bacteria and bacteriophages have shown that many point mutational events involve guanine to adenine transitions, and the most abundant reaction product found in acid hydrolysates of treated DNA is 7-alkyl Guanine.
Abstract: BIOLOGICAL alkylating agents—“mustards”, ethylenimines, epoxides and alkyl alkanesulphonates—have been believed to induce mutations by causing atypical base pairing during DNA replication at sites bearing a guanine residue which has suffered alkylation at the 7(N) position1,2. The most abundant reaction product found in acid hydrolysates of treated DNA is 7-alkyl guanine3,4, although alkylated adenines and cytosine, notably 3-alkyl adenine, are recovered as minor products. Furthermore, genetic studies of alkylation mutants in bacteria and bacteriophages have shown that many point mutational events involve guanine to adenine transitions5,6.
913 citations
TL;DR: Evidence for the Binding of Polynuclear Aromatic Hydrocarbons to the Nucleic Acids of Mouse Skin : Relation between Carcinogenic Power of hydrocarbons and their Binding to Deoxyribonucleic Acid is presented.
Abstract: Evidence for the Binding of Polynuclear Aromatic Hydrocarbons to the Nucleic Acids of Mouse Skin : Relation between Carcinogenic Power of Hydrocarbons and their Binding to Deoxyribonucleic Acid
659 citations
TL;DR: Both in vitro and in cells about 7% of the methylation of DNA by MNNG occurs at the 6-oxygen atom of guanine, but dimethyl sulphate does not yield O(6)-methylguanine.
Abstract: 1. In neutral aqueous solution N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) yields salts of nitrocyanamide as u.v.-absorbing products. With cysteine, as found independently by Schulz & McCalla (1969), the principal product is 2-nitraminothiazoline-4-carboxylic acid. Both these reactions liberate the methylating species; thiols enhance the rate markedly at neutral pH values. An alternative reaction with thiols gives cystine, presumably via the unstable S-nitrosocysteine. 2. Thiols (glutathione or N-acetylcysteine) in vitro at about the concentration found in mammalian cells enhance the rate of methylation of DNA markedly over that in neutral solution. 3. Treatment of cultured mammalian cells with MNNG results in rapid methylation of nucleic acids, the extent being greater the higher the thiol content of the cells. Rodent embryo cells are more extensively methylated than mouse L-cells of the same thiol content. Cellular thiol concentrations are decreased by MNNG. Proteins are less methylated by MNNG than are nucleic acids. 4. Methylation of cells by dimethyl sulphate does not depend on cellular thiol content and protein is not less methylated than nucleic acids. Methylation by MNNG may therefore be thiol-stimulated in cells. 5. Both in vitro and in cells about 7% of the methylation of DNA by MNNG occurs at the 6-oxygen atom of guanine. The major products 7-methylguanine and 3-methyladenine are given by both MNNG and dimethyl sulphate, but dimethyl sulphate does not yield O(6)-methylguanine. Possible reaction mechanisms to account for this difference between these methylating agents and its possible significance as a determinant of their biological effects are discussed.
474 citations
TL;DR: A genetic demonstration is presented that thymine starvation leads to the initiation of a new round of DNA replication, even if the chromosome is already being replicated at the time thymine is withheld.
288 citations
TL;DR: Molecular Mechanism of the Cytotoxic Action of Difunctional Alkylating Agents and of Resistance to this Action are studied.
Abstract: Molecular Mechanism of the Cytotoxic Action of Difunctional Alkylating Agents and of Resistance to this Action
256 citations