A Polymerase – Tautomeric Model for Targeted Frameshift Mutations: Deletions Formation during Error-prone or SOS Replication of Double-stranded DNA Containing cis-syn Cyclobutane Thymine Dimers

Abstract

Now it is still unclear how frameshift mutations arise at cyclobutane pyrimidine dimers. The author develops polymerase -tautomeric model of ultraviolet mutagenesis. The model is described that is based on the formation of rare tautomeric bases in cis-syn cyclobutane thymine dimers. A mechanism was proposed for targeted deletions caused by cis-syn cyclobutane thymine dimers. Targeted deletions are frameshift mutations when one or several nucleotides are dropped out in a DNA site opposite to a lesion capable of stopping DNA synthesis. Ultraviolet irradiation may result in changes of tautomer states of DNA bases. Thymine molecule may form 5 rare tautomer forms. They are stable if these bases are part of cyclobutane dimers. Structural analysis indicates that opposite one type of cis-syn cyclobutane thymine dimers containing a single tautomeric base (TT 2 *, with the '*' indicating a rare tautomeric base and the subscript referring to the particular conformation) it is impossible to insert any canonical DNA bases with the template bases with hydrogen bonds formation. Therefore it is proposed that under synthesis DNA containing cis-syn cyclobutane thymine dimers TT 2 * specialize or modified DNA polymerases will leave one nucleotide gaps opposite these cis-syn cyclobutane thymine dimers. Daughter DNA strand opposite cis-syn cyclobutane thymine dimers TT 2 * may fall out. If in opposite DNA strand the loop is formed, daughter strand becomes shorter. Some DNA nucleotides are lost. Targeted deletion is formed. According to the polymerase-tautomeric model of ultraviolet mutagenesis cis-syn cyclobutane thymine dimers wherein a thymine is in the canonical tautomeric forms do not result in mutations. Cis-syn cyclobutane thymine dimers wherein a thymine is in the rare tautomeric forms T 1 *, T 4 *, or T 5 * were shown to cause only targeted base substitution mutations. Cis-syn cyclobutane thymine dimers wherein a thymine is in the rare tautomeric form T 2 * may result in targeted frameshift mutations (targeted insertions and targeted deletions).

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“…The polymerase-tautomeric model for targeted mutagenesis is able to explain the mechanisms formation for targeted substitution mutations, 42,76 targeted insertions, 42,79 targeted deletions 42,80 and targeted complex insertions. 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.…”

“…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.…”

“…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.…”

Paradigm change in mutagenesis: polymerase tautomeric models for targeted, delayed and untargeted ultraviolet mutagenesis during error plication of double stranded DNA, containing cis-syn cyclobutane thymine dimers or thymine in rare tautomeric forms

“…It was concluded that there are rare tautomeric forms of cytosine in the investigated crystals 39 However, all currently existing mutagenesis models cannot explain most of the phenomena of mutagenesis. 41,42 Polymerase paradigm. [27][28][29] tautomer model by Watson and Crick [34][35][36][37] and deamination model [30][31][32] claim an explanation targeted base substitution mutations only.…”

“…[27][28][29] tautomer model by Watson and Crick [34][35][36][37] and deamination model [30][31][32] claim an explanation targeted base substitution mutations only. Cyclobutane pyrimidine dimer consisting deamination cytosine or 5-methylcytosine [30][31][32][33][34][35][36][37][38][39][40][41][42][43] may result in base substitution mutations. Some data implicate the deamination of cytosine to uracil as a possible cause, but other results appear to indicate that the rate of deamination is too low (in the range of 10 -10 sec -1 by in vitro measurement) for this to be significant in Escherichia coli.…”