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Control of the initiation of 
DNA replication. The replication origin is 
bound by the origin recognition complex 
(ORC) throughout the cell cycle, but ORC 
functions only in late mitosis and early G1 
when it associates with Cdc6. ORC–Cdc6 
binds the Mcm helicase, which contains 
six closely related subunits arranged in a 
barrel shape. The helicase also associates 
with a protein called Cdt1. Using energy 
provided by ATP hydrolysis, the ORC and 
Cdc6 proteins load two copies of the Mcm 
helicase around the DNA next to the origin. 
At the onset of S phase, S-Cdk stimulates 
the assembly of several accessory 
proteins, including Cdc45 and GINS, 
on each Mcm helicase. Another protein 
kinase, DDK, phosphorylates subunits of 
the Mcm helicase. The result is a large 
protein complex called the CMG helicase 
(for Cdc45–Mcm–GINS), which unwinds 
the DNA at the origin. DNA polymerase 
and other replication proteins arrive at 
the origin, and DNA replication begins. 
For clarity, this diagram does not show 
synthesis of the lagging strand (discussed 
in Chapter 5). The ORC is displaced by 
the replication machinery, but new ORCs 
bind to both replication origins after their 
replication. S-Cdk and other mechanisms 
also inactivate the loading factors ORC, 
Cdc6, and Cdt1, thereby preventing 
loading of new Mcm helicases at the 
origins until the end of mitosis.