Passive polymerase control of DNA replication fidelity: evidence against unfavored tautomer involvement in 2-aminopurine-induced base-transition mutations.

Abstract

We consider the role of unfavored tautomers in causing base-substitution transition mutations. Data obtained with the base analogue 2-aminopurine (AP) for the frequency of forming AP.T and AP.C base mispairs can be shown to be in probable conflict with tautomer model predictions. An alternative model, in which individual hydrogen bonds exhibit different bond strengths depending upon their ring position, is proposed to account for the frequencies of forming correct and incorrect base pairs. In this "differential H-bonding" model, disfavored tautomers of AP and those of common nucleotides play a generally insignificant role. A hydrogen-bonding free energy scale is derived in which free energy differences are obtained for all possible matched and mismatched base pairs. We also show that recent in vitro data for the formation of AP.C base pairs are consistent with a "passive polymerase" theoretical model in which base selection is governed not by the enzyme but by differences in base-pairing free energies.