The eukaryotic bell-shaped temporal rate of DNA replication origin firing emanates from a balance between origin activation and passivation

Before a cell can divide, it must duplicate its DNA. In eukaryotes – organisms such as animals and fungi, which store their DNA in the cell’s nucleus – DNA replication starts at specific sites in the genome called replication origins. At each origin sits a protein complex that will activate when it randomly captures an activating protein that diffuses within the nucleus. Once a replication origin activates or “fires”, the complex then splits into two new complexes that move away from each other as they duplicate the DNA. If an active complex collides with an inactive one at another origin, the latter is inactivated – a phenomenon known as origin passivation. When two active complexes meet, they release the activating proteins, which diffuse away and eventually activate other origins in unreplicated DNA. The number of origins that activate each minute divided by the length of unreplicated DNA is referred to as the “rate of origin firing”. In all eukaryotes, this rate – also known as I(t) – follows the same pattern. First, it increases until more than half of the DNA is duplicated. Then it decreases until everything is duplicated. This means that, if plotted out, the graph of origin firing rate would always be a bell-shaped curve, even for organisms with genomes of different sizes that have different numbers of origins. The reason for this universal shape remained unclear. Scientists had tried to create numerical simulations that model the rate of origin firing. However, for these simulations to reproduce the bell-shape curve, a number of untested assumptions had to be made about how DNA replication takes place. In addition, these models ignored the fact that it takes time to replicate the DNA between origins. To take this time into account, Arbona et al. instead decided to model the replication origins as discrete and distinct entities. This way of building the mathematical model succeeded in reproducing the universal bell curve shape without additional assumptions. With this simulation, the balance between origin activation and passivation is enough to achieve the observed pattern. The new model also predicts that the maximum rate of origin firing is determined by the speed of DNA replication and the density of origins in the genome. Arbona et al. verified this prediction in yeast, fly, frog and human cells – organisms with different sized genomes that take between 20 minutes and 8 hours to replicate their DNA. Lastly, the prediction also held true in yeast treated with hydroxyurea, an anticancer drug that slows DNA replication. A better understanding of DNA replication can help scientists to understand how this process is perturbed in cancers and how drugs that target DNA replication can treat these diseases. Future work will explore how the 3D organization of the genome affects the diffusion of activating proteins within the cell nucleus.