Mechanistic clues to the mutagenicity of alkylated DNA bases: a theoretical study.
TL;DR: Experiment indicates that the N7-guanine site in DNA is not "promutagenic" (mutation-inducing) on alkylation, while the O6- guanine and O4-thymine sites are so, thus accounting for observed differences in promutagenicity and nucleic acid template activity.
About: This article is published in Journal of Theoretical Biology.The article was published on 1989-10-09. It has received 12 citations till now. The article focuses on the topics: Nucleic acid.
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TL;DR: In this article, it was suggested that the spontaneous formation of apyrimidinic sites in nucleic acids take place via prior protonation of guanine moieties in the opposite strand.
Abstract: AM1 calculations have been used to study the effects of protonation on the structures, energies, and, in some cases, proton transfer reactions of guanine cytosine base pairs. Protonation at the guanine O6-position, or at various ring sites, leads to a relatively facile conversion to a surprisingly stable complementary base pairs following proton transfer to the cytosine 3-position. In the case of O6-protonation, this constitutes a direct route to guanine enolization. It is suggested that the spontaneous formation of apyrimidinic sites in nucleic acids take place via prior protonation of guanine moieties in the opposite strand. © 1992 John Wiley & Sons, Inc.
18 citations
TL;DR: The prediction that N3- and O6-methylguanines and O2 and O4-methylthymines would be promutagenic bases at biological pH, while N1- methylguanine would behave without miscoding properties is made.
Abstract: The products of methylation at the N3-, O6- and N7-positions of guanine and at the O2- and O4- positions of thymine are subjected to various possibilities for pairing with DNA bases, using calculations at the semiempirical PM3 SCF-MO level. It is predicted that the presence of the Watson–Crick protons in the modified bases would lead to non-mutagenic base-pairing schemes, while their absence facilitates promutagenic pairing schemes, modified guanines behaving like adenine and modified thymines like cytosine. Some degree of competition with non-mutagenic base-pairing schemes is also anticipated. Only the conformers of the O-methylated bases with the O-methyl group anti to the hydrogen bonding side furnish feasible base-mispairing schemes in the double-helical configuration. The syn conformers do not pair in the double-helical configuration. Correlation of these results with experimental and theoretically predicted Watson–Crick proton acidities for the nucleoside systems leads to the prediction that N3- and O6-methylguanines and O2 and O4-methylthymines would be promutagenic bases at biological pH, while N1-methylguanine would behave without miscoding properties. These predictions are largely confirmed by the reported experimental template properties of these modified DNA bases and are also corroborated by NMR, UV and crystallography studies on some of the modified bases considered here.
15 citations
TL;DR: A model for ultraviolet mutagenesis is described that is based on the formation of rare tautomeric bases in pyrimidine dimers and it is shown that during SOS synthesis the modified DNA‐polymerase inserts canonical bases opposite the dimers; the inserted bases are capable of forming hydrogen bonds with bases in the template DNA.
Abstract: A model for ultraviolet mutagenesis is described that is based on the formation of rare tautomeric bases in pyrimidine dimers. It is shown that during SOS synthesis the modified DNA-polymerase inserts canonical bases opposite the dimers; the inserted bases are capable of forming hydrogen bonds with bases in the template DNA. SOS-replication of double-stranded DNA having thymine dimers, with one or both bases in a rare tautomeric conformation, results in targeted transitions, transversions, or one-nucleotide gaps. Structural analysis indicates that one type of dimer containing a single tautomeric base (TT*(1), with the "*" indicating a rare tautomeric base and the subscript referring to the particular conformation) can cause A:T --> G:C transition or homologous A:T --> T:A transversion, while another dimer (TT*(2)) can cause a one-nucleotide gap. The dimers containing T*(4) result in A:T --> C:G transversion, while TT*(5) dimers can cause A:T --> C:G transversion or homologous A:T --> T:A transversion. If both bases in the dimer are in a rare tautomeric form, then tandem mutations or double-nucleotide gaps can be formed. The dimers containing the rare tautomeric forms T*'(1) , T*'(2), T*'(3), T*'(4), and T*'(5) may not result in mutations. The question of whether dimers containing T*'(4) and T*'(5) result in mutations requires further investigation.
10 citations
TL;DR: In this paper, a semi-empirical molecular orbital study was conducted to examine the various possibilities open for these protic changes in a number of methylated guanines and thymines and their deoxynucleosides.
Abstract: Proton changes have been advanced as being the key molecular basis for the mutagenecity of alkylated DNA bases and nucleosides, leading to questions as to which protons are involved and whether the protic changes are tautomeric shifts or abstractions. This semiempirical molecular orbital study seeks to clarify the issue by examining the various possibilities open for these protic changes in a number of methylated guanines and thymines and their deoxynucleosides. Proton shifts leading to tautomer formation are not predicted as being thermodynamically favourable in most cases. The most feasible proton abstractions are predicted to involve the Watson-Crick protons in all cases, which corroborates Watson-Crick proton loss as providing the key molecular basis for the induction of point mutations. The calculated proton acidities correlate well with experimental data. The gas-phase deprotonation enthalpies for a number of alkylated nucleosides are found to correlate linearly with the solvent-phase pK(a) values. The theoretically calculated enthalpies in a simulated aqueous solvent phase of the deprotonation reactions of various nucleic acid bases are also found to have good linear correlations with experimental pK(a) values. The consensus of these calculations is that O-6-alkyldeoxyguanosines, and O-2- and O-4-alkyldeoxythymidines would be mutagenic while N-7-alkyldeoxyguanosines would not be mutagenic (as experiment indicates). The untested N-3-methyldeoxyguanosine is predicted to be mutagenic. (C) 1997 Elsevier Science B.V.
8 citations
References
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TL;DR: The Intermediate Neglect of Differential Overlap (INDO) method proposed in this article is an improvement over the CNDO method, in that atomic term-level splittings and unpaired spin distributions are better accommodated.
Abstract: A new approximate self‐consistent‐field method for the determination of molecular orbitals for all valence electrons of a molecule is proposed. This method features neglect of differential overlap in all electron‐interaction integrals except those involving one center only. The parameters involved in the calculation are generally obtained semi‐empirically. The new method is known as the Intermediate Neglect of Differential Overlap (INDO) method, and may be regarded as an improvement over the CNDO method proposed in Part I, in that atomic term‐level splittings and unpaired spin distributions are better accommodated. Calculations on geometries of AB2 and AB3 molecules are reported to substantiate the proposed method, and calculated unpaired spin distributions for methyl and ethyl radicals are discussed.
1,380 citations
1,319 citations
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: The absence of net charge on the freelycirculating blood-stream form of T. rhodesiense is evidence that van der Waals forces play a very minor role in cell adhesion, although the flagellate motility may adversely influence the adhesion process.
Abstract: Prothidium caused gross loss of motility and clumping of all trypanosomes. Comparison of the findings for trypanosomes with those for other cells previously studied shows that T. Iewi8i iS very similar electrophoretically to freely circulating cells such as lymphocytes and tumour cells. On the other hand, the surface properties of the blood-stream form of T. rhodesiense are different electrophoretically from any other freely circulating cell so far studied. If the surface of these cells does contain carboxyl groups, the previous hypothesis that all cells carrying surface carboxyl groups will be adhesive to phagocytes will need modification (Bangham & Pethica, 1960). The absence of net charge on the freelycirculating blood-stream form of T. rhodesiense is evidence that van der Waals forces play a very minor role in cell adhesion (Pethica, 1961), although the flagellate motility may adversely influence the adhesion process.
713 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