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

Abstract

The time-dependent rate <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>I</mml:mi> <mml:mo>(</mml:mo> <mml:mi>t</mml:mi> <mml:mo>)</mml:mo> </mml:mrow> </mml:math> of origin firing per length of unreplicated DNA presents a universal bell shape in eukaryotes that has been interpreted as the result of a complex time-evolving interaction between origins and limiting firing factors. Here, we show that a normal diffusion of replication fork components towards localized potential replication origins (p-oris) can more simply account for the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>I</mml:mi> <mml:mo>(</mml:mo> <mml:mi>t</mml:mi> <mml:mo>)</mml:mo> </mml:mrow> </mml:math> universal bell shape, as a consequence of a competition between the origin firing time and the time needed to replicate DNA separating two neighboring p-oris. We predict the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>I</mml:mi> <mml:mo>(</mml:mo> <mml:mi>t</mml:mi> <mml:mo>)</mml:mo> </mml:mrow> </mml:math> maximal value to be the product of the replication fork speed with the squared p-ori density. We show that this relation is robustly observed in simulations and in experimental data for several eukaryotes. Our work underlines that fork-component recycling and potential origins localization are sufficient spatial ingredients to explain the universality of DNA replication kinetics.