Network diagram for the initiation of DNA replication. Chromatin-bound species are shown in yellow. Reactions that we have considered reversible are shown with an arrowhead at each end. ORC-bound DNA (RC1) specifies a complex that has bound origin sequences following DNA replication of the previous cycle. Cdc6 reversibly binds ORC-bound DNA starting in late M-phase to form RC2. The Mcm2-7 hexamers, chaperoned by Cdt1 are localized to origins where they are loaded onto the double helix (RC3). Cdt1 is later exported from the nucleus by a CDK-dependent mechanism (i.e. by Clb5-Cdc28). Free Cdc6 is targeted for proteolysis in a CDK-dependent manner. Upon Cdc6 dissociation, the complex of MCM and ORC (RC4) is also subject to dissociation. RC4 awaits association of and activation by a complex of Dbf4 and Cdc7 (DDK), which phosphorylates various MCM subunits (RC5). Required ultimately for the stabilization of DNA polymerase, Cdc45 binds in response to specific CDK phosphorylation events (RC6, also called the Pre-IC). DNA replication begins as forks are established (FORK). Dbf4 dissociates soon after initiation and is constitutively degraded throughout S-phase. Its levels cannot rise until late G1 since it is actively targeted for degradation by APCCdc20, whose low in G1 are sufficient for this inhibition. Once a replication fork terminates, both Cdc45 and the MCM fall off the chromatin. Free MCM is exported to the cytoplasm via a CDK-dependent mechanism. ORC is phosphorylated by CDK (RC7) and cannot interact with pre-RC components until it is dephosphorylated, returning it to the RC1 state.