Computer simulations reveal mechanisms of spatio-temporal regulation of DNA replication

The dynamics of DNA replication, activation of replication origins and elongation rate, depend on dNTP in ways that remain poorly understood. Here, we present RepliSim, a probabilistic computer model of DNA replication simulation, which is capable of simulating DNA replication not only in normal conditions, but also during perturbations (e.g. HU treatment) and in mutant cells (here checkpoint deficient yeast cells). We show that different mutations in checkpoint genes, affect the origin activation differently by modulating the stochasticity of firing time and efficiency, regardless of the dNTP levels. The origin activation is less affected by increase in dNTP levels, however it declined drastically during the S phase when the dNTP levels decreased compared to G1 phase. Additionally, we show that the distribution of distances covered by replication forks is influenced not only by average fork progression speed, but also by firing time and fork progression speed stochasticity, while the latter has been neglected in most of the proposed models for DNA replication. These together, opens up new insight to the studies about the dynamics of replication and how it is coordinated during the S-phase.