A Polymerase Tautomeric Model for Radiation Induced Bystander Effects: A Model for Untargeted Base Substitution Mutagenesis during Error Prone and SOS Replication of Double Stranded DNA Containing Thymine and Adenine in Rare Tautomeric Forms

Abstract

Currently, untargeted mutations are studied in the context of bystander effects. Up to now the nature and mechanisms of formation of untargeted mutations is poorly understood. Untargeted base substitution mutations are base substitution mutations then one or some nucleotides are inserted in DNA molecule on, so called, undamaged sites of DNA. Here the polymerase-tautomeric models of ultraviolet mutagenesis and bystander effects are developed. The mechanisms of untargeted base substitution mutations formation caused by cis-syn cyclobutane thymine dimers and bases pairs of adenine-thymine or thymine-adenine in rare tautomeric forms that are in small neighbor from any cyclobutane dimers are proposed. Five rare tautomeric forms may form for thymine and adenine. These rare tautomeric forms will be stable if corresponding nucleotides are part of cyclobutane pyrimidine dimers or are in small neighbor of the cyclobutane dimers and during DNA synthesis. Structural analysis of bases incorporation shown that adenine in rare tautomeric form A 1

Untitled

“…42,81 The polymerasetautomeric models for radiation induced genomic instability is able to explain the mechanisms formation for targeted delayed base substitution mutations. 42,86 The polymerase-tautomeric model for radiation-induced bystander effects is able to explain the mechanisms formation for untargeted substitution mutations 84 and untargeted insertions. 85 Untargeted mutations appear opposite DNA bases in rare tautomeric forms located, for example, near (2-3 bases) from cyclobutane dimers.…”

“…42,86 The polymerase-tautomeric model for radiation-induced bystander effects is able to explain the mechanisms formation for untargeted substitution mutations 84 and untargeted insertions. 85 Untargeted mutations appear opposite DNA bases in rare tautomeric forms located, for example, near (2-3 bases) from cyclobutane dimers. It is observed a thymine-guanine (T•G) 61 and a cytosine-adenine (C•A) 62 base pairs with one of the bases in rare tautomeric forms in the active site of DNA polymerases.…”

“…61,62 The results of studies on the structure of the active centers polymerases show that the bases in rare tautomeric forms may exist in the active sites of DNA polymerases. 61,62 These results served as the basis for the development of the polymerase-tautomeric models for targeted ultraviolet mutagenesis, 41,42,50,63,69,70,72,73,75,76,[78][79][80][81][82] radiation-induced bystander effects 71,74,77,84,85 and radiation-induced genomic instability. 49,63,83,86 The polymerase-tautomeric models are based on Watson and Crick's hypothesis that the mutagenesis is based on the ability of the bases to change the tautomeric state.…”

“…The polymerase-tautomeric model for the mechanism of the formation of untargeted insertions caused by thymine and adenine in certain rare tautomeric forms is proposed. 85 Structural analysis indicates that opposite the rare tautomers of thymine T 2 * ( Figure 4) and adenine A 3 * it is impossible to insert any canonical base so that hydrogen bonds between the rare tautomers of thymine T 2 * or adenine A 3 * and the canonical bases of DNA are formed. In doing so, author based on the following facts.…”

“…As a result, the daughter strand is elongated leading to untargeted insertion (Figure 9). 85 The polymerase tautomeric model for bystander effects is able to explain the mechanisms formation for untargeted base substitution mutations and untargeted insertions.…”