f = m*a: A Framework for Investigating the Regulation of Replication Timing

Stochastic models of replication timing posit that origin firing timing is regulated by origin firing probability, with early-firing origins having a high probability of firing and late-firing origins having a lower probability. However, they offer no insight into why one origin should have a higher firing probability than another. Here, a simple framework is suggested for how to approach the question by noting that the firing probability (f) must be the product of the stoichiometry of the MCM replicative helicase loaded at the origin (m) and the probability with which that MCM is activated (a). This framework emphasizes that mechanistic understanding of replication timing must focus on MCM loading and activation and can be simplified to the equation f = m*a.