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 (TT2*, 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 TT2* 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 TT2* 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 T1*, T4*, or T5* were shown to cause only targeted base substitution mutations. Cis-syn cyclobutane thymine dimers wherein a thymine is in the rare tautomeric form T2* may result in targeted frameshift mutations (targeted insertions and targeted deletions).