A model for targeted substitution mutagenesis during SOS replication of double‐stranded DNA containing cis‐syn cyclobutane thymine dimers

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.

DFT studies on the favored and rare tautomers of neutral and redox cytosine

“…It is well recognized that prototropy in nucleobases influences the structure of nucleic acids and their replication, mutation, and degradation processes [1][2][3][4][5][6][7][8][9][10][11][12][13]. Labile hydrogens can move as protons between conjugated sites and change properties of nucleobases, particularly their ability to H-bonding.…”

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

“…It has been proved in detail for the case when the DNA molecule is irradiated with ultraviolet light [79][80][81][82][83]98,99]. After irradiation of DNA by ultraviolet light excitation energy ultimately localized on one of the bases.…”

“…At the second stage, the formed rare metastable tautomeric states transform into the stable ones. Allowance the predicted [119] a metastable state leading to that rare tautomeric forms of thymine T* 4 and T* 5 and rare tautomeric forms of adenine А* 4 and А* 5 ( Figure 2) [82,83] can be formed. Double-stranded DNA contains the guanine-cytosine and adenine-thymine base pairs.…”

“…This means that there is change of tautomeric states of bases, and it will be stable [80][81][82][83][84].…”

“…Five new rare tautomeric conformations of the adenine and thymine [81,82], they shown on Figure 1, and seven of the cytosine and guanine [80,83]. Such rare tautomeric forms of DNA bases are stable when they are parts of the cis-syn cyclobutane pyrimidine dimers and they are stable under DNA synthesis [81][82][83][84].…”