# Regulation of replication timing in Saccharomyces cerevisiae

## TL;DR

This paper introduces a computational model to study how DNA replication timing is regulated in yeast, focusing on competition for limited replication proteins.

## Contribution

A high-resolution stochastic model of DNA replication in yeast that captures origin competition for firing factors.

## Key findings

- The model accurately reproduces experimental features like inter-origin distances and replication fork directionality.
- It predicts unmeasured DNA replication dynamics and the impact of firing factor concentration variations.
- The model identifies key factors influencing replication timing with minimal complexity.

## Abstract

In order to maintain genomic integrity, DNA replication must be highly coordinated. Disruptions in this process can cause replication stress which is aberrant in many pathologies including cancer. Despite this, little is known about the mechanisms governing the temporal regulation of DNA replication initiation, thought to be related to the limited copy number of firing factors. Here, we present a high (1-kilobase) resolution stochastic model of Saccharomyces cerevisiae whole-genome replication in which origins compete to associate with limited firing factors. After developing an algorithm to fit this model to replication timing data, we validated the model by reproducing experimental inter-origin distances, origin efficiencies, and replication fork directionality. This suggests the model accurately simulates the aspects of DNA replication most important for determining its dynamics. We also use the model to predict measures of DNA replication dynamics which are yet to be determined experimentally and investigate the potential impacts of variations in firing factor concentrations on DNA replication.

Each time a cell divides, it is essential that its entire genome is copied accurately. The timing of this DNA replication must be highly coordinated, and disruptions to this process are common in many diseases, including cancer. Despite its vital importance, what controls this coordination is still not fully understood. One idea is that the potential sites where replication can start must compete with each other for a limited supply of essential proteins. To explore this, we created a computational model that simulates whole-genome replication in budding yeast. In our model, potential starting points for replication compete to bind with a limited number of essential proteins. We show that the model can reproduce known features of DNA replication dynamics and also predict aspects of the process that have not yet been measured experimentally. By making the model as simple as possible while still capturing the key features of DNA replication, we identify the factors most important for determining replication timing. Our model provides a useful tool for investigating how replication is coordinated and may help to guide future research.