Mutagenic DNA Repair: Insertion of Nucleotides Opposite Non-coding Template Structures by a Reversed 3'-5' Exonuclease Reaction? A Hypothesis

Abstract

1. The enzymatic mechanism of mutagenic DNA repair is unknown. None of the characterized DNA polymerases is capable of polymerization past non-coding template structures. 2. A hypothesis is proposed according to which polymerization opposite non-coding template structures is catalyzed by the DNA-polymerase-associated 3'-5' exonuclease under conditions which shift the equilibrium of the 3'-5' exonuclease reaction DNAn + H2O in equilibrium DNAn-1 + dNMP to the left, i.e. to the incorporation of deoxynucleoside monophosphates. 3. Conditions which favor the incorporation of dNMP by the reversed 3'-5' exonuclease reaction include a high dNMP concentration, a coupled H2O-consuming reaction and a hydrophobic enzyme environment. 4. The statements of the hypothesis are supported by published work on the biochemistry of DNA polymerases and their associated 3'-5' exonucleases, the genetics of mutagenic DNA repair and the involvement of Escherichia coli DNA polymerase III in this process. 5. The hypothesis offers an explanation of the mutator and antimutator properties of certain genes, in particular of DNA polymerase genes, and also explains how some drugs act mutagenically during DNA replication and antimutagenically against mutagenic DNA repair.