Figure 4.

Model for regulation of replication timing by MCM loading and heterochromatin. Origins at which many MCMs are loaded are more likely to fire in early S and therefore have an early average firing time; origins at which fewer MCMs are loaded are less likely to fire in early S and therefore have a later average firing time. High-affinity origins are bound by ORC for more of G1 and therefore may have more MCMs loaded. Heterochromatin provides a second layer of regulation, on top of our proposed MCM-based mechanism. Heterochromatin could delay origin firing at any step in the origin licensing/firing cycle—ORC binding, MCM loading, or MCM activation—but the observation that many MCMs are loaded at heterochromatically silenced telomeric origins suggests that one way heterochromatin delays replication time is by inhibiting activation of loaded MCMs.