Abstract
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.
Highlights
A stochastic model can describe the experimental observations of reproducible replication timing and heterogeneous origin firing, it provides no insight into the key mechanistic question it raises: How is the probability of origin firing regulated? One way to approach the problem is to observe that the rate-limiting step for origin firing is the activation of the MCM replicative helicase
The varying probability of origin firing, which is observed in yeast and humans [2,5,6], provides a mechanistic explanation for the regulation of replication timing, as described above, both for the well-defined origins of budding yeast and the broad initiation zones of mammalian cells [3,7,11,13]
In mammalian genomes, in which timing correlates well with chromatin structure, MCM activatability may play the dominant role in regulating replication timing, the rate of MCM loading has been reported to vary between euchromatin and heterochromatin [55]
Summary
A stochastic model can describe the experimental observations of reproducible replication timing and heterogeneous origin firing, it provides no insight into the key mechanistic question it raises: How is the probability of origin firing regulated? One way to approach the problem is to observe that the rate-limiting step for origin firing is the activation of the MCM replicative helicase. The regulation of origin firing by limiting factors explains why origins fire with low probability.
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