Figure 7. Origin activation and replication fork unwinding by the CMG helicase.

Origin licensing involves the loading of a head-to-head double hexameric ring that encircles duplex DNA, which might become partially deformed. Cdc45 is loaded onto the double hexamer, in a process that requires DDK phosphorylation of MCM. DDK phosphorylation might cause a rearrangement in Mcm5 and disrupt the (yeast specific) Mcm5-7 trans interaction. This rearrangement would expose a GINS interacting element in Mcm5. ATP hydrolysis by the MCM promotes the relative rotation of the NTD and AAA+ tiers of the helicase, in a movement that might promote duplex DNA underwinding. Following a poorly understood lagging-strand extrusion process, the CMG helicase extensively unwinds the replication fork, by translocating on single-stranded DNA.