Mutagenic DNA repair: insertion of nucleotides opposite non-coding template structures by a reversed 3'-5'...

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• The enzymatic mechanism of mutagenic DNA repair is not understood.
• Standard DNA polymerases cannot synthesize DNA past non-coding template lesions.
• Escherichia coli DNA polymerase III is implicated in mutagenic DNA repair.

Purpose of the Study:

• To propose a novel hypothesis for the enzymatic mechanism of mutagenic DNA repair.
• To explain the role of DNA polymerase-associated exonucleases in DNA repair.
• To elucidate the basis for mutator/antimutator gene properties and drug effects.

Main Methods:

• Literature review of DNA polymerase biochemistry and genetics.
• Analysis of published data on DNA repair mechanisms.
• Hypothetical modeling of enzymatic reactions.

Main Results:

• A hypothesis is proposed where the 3"-5" exonuclease activity of DNA polymerases catalyzes polymerization by reversing its reaction.
• Conditions favoring this reversed exonuclease activity include high deoxynucleoside monophosphate (dNMP) concentration, coupled water-consuming reactions, and a hydrophobic enzyme environment.
• The hypothesis is supported by existing literature on DNA polymerases, exonucleases, and mutagenic repair.

Conclusions:

• The proposed mechanism explains how DNA polymerases can synthesize DNA past non-coding templates.
• This hypothesis accounts for the mutator and antimutator phenotypes associated with DNA polymerase genes.
• The model provides insights into the mutagenic and antimutagenic actions of certain drugs during DNA replication and repair.