Accuracy and speed of elongation in a minimal model of DNA replication

TL;DR

This paper presents a minimal kinetic model of DNA replication, analyzing how enzyme activities influence the speed and accuracy of DNA elongation, and explores how different discrimination modes can optimize replication fidelity.

Contribution

It introduces an exact analytical model of DNA polymerase activity, including exonuclease function, to understand the coordination of speed and accuracy in DNA replication.

Findings

Accuracy depends on kinetic competition between stepping and unbinding.

Inclusion of exonuclease activity can improve accuracy with minimal speed loss.

Designs can bypass the speed-accuracy trade-off in certain parameter regimes.

Abstract

Being a dual purpose enzyme, the DNA polymerase is responsible for elongation of the newly formed DNA strand as well as cleaving the erroneous growth in case of a misincorporation. The efficiency of replication depends on the coordination of the polymerization and exonuclease activity of DNA polymerase. Here we propose and analyze a minimal kinetic model of DNA replication and determine exact expressions for the velocity of elongation and the accuracy of replication. We first analyze the case without exonuclease activity. In that case, accuracy is determined by a kinetic competition between stepping and unbinding, with discrimination between correct and incorrect nucleotides in both transitions. We then include exonuclease activity and ask how different modes of additional discrimination in the exonuclease pathway can improve the accuracy while limiting the detrimental effect of exonuclase on the speed of replication. In this way, we ask how the kinetic parameters of the model have to be set to coordinate the two activities of the enzyme for high accuracy and high speed. The analysis also shows that the design of a replication system does not universally have to follow the speed-accuracy trade-off rule, although it does in the biologically realized parameter range. The accuracy of the process is mainly controlled by the crucial role of stepping after erroneous incorporation, which has impact on both polymerase and exonuclease activities of DNA polymerase.