Theory of Semi-discontinuous DNA Replication

TL;DR

This paper develops a stochastic framework to analyze semi-discontinuous DNA replication, focusing on the dynamics of lagging-strand polymerase and Okazaki fragment formation, with application to T4 bacteriophage data.

Contribution

It introduces a novel stochastic model for lagging-strand polymerase dynamics and characterizes Okazaki fragment size distribution.

Findings

Polymerase dissociation is mainly triggered by collisions with Okazaki fragments.

The model accurately predicts fragment size distributions observed in experiments.

Key parameters influencing polymerase behavior are identified.

Abstract

In biological cells, DNA replication is carried out by the replisome, a protein complex encompassing multiple DNA polymerases. DNA replication is semi-discontinuous: a DNA polymerase synthesizes one (leading) strand of the DNA continuously, and another polymerase synthesizes the other (lagging) strand discontinuously. Complex dynamics of the lagging-strand polymerase within the replisome result in the formation of short interim fragments, known as Okazaki fragments, and gaps between them. Although the semi-discontinuous replication is ubiquitous, a detailed characterization of it remains elusive. In this work, we develop a framework to investigate the semi-discontinuous replication by incorporating stochastic dynamics of the lagging-strand polymerase. Computing the size distribution of Okazaki fragments and gaps, we uncover the significance of the polymerase dissociation in shaping them. We apply the method to the previous experiment on the T4 bacteriophage replication system and identify the key parameters governing the polymerase dynamics. These results reveal that the collisions of lagging-strand polymerase with pre-synthesised Okazaki fragments primarily trigger its dissociation from the lagging strand.