FIGURE 19-16 The molecular mechanisms governing the initiation of DNA replication. Step 1: During exit from mitosis and early G₁, when CDK activity is low, the MCM loading factors ORC, Cdc6, and Cdt1 load the replicative helicase, the MCM complex, onto DNA at replication origins. Step 2: Activation of S phase CDKs and DDK marks the onset of S phase. They phosphorylate the MCM helicase, Sld2, and Sld3 (depicted as green phosphorylation events), to facilitate the loading of MCM helicase activators—the Cdc45-Sld3 and GINS complexes—onto sites of replication initiation. Loading of these activators leads MCM helicases to unwind DNA. S phase CDKs also prevent reloading of MCM helicases by phosphorylating Cdc6 and Cdt1 (shown as yellow phosphorylation events), promoting their release from the replication origins and their degradation by SCF. S phase CDKs also phosphorylate MCM helicases, which leads to their export from the nucleus when the helicases disengage from the DNA when replication is complete. Step 3: DNA polymerases are recruited to origins, which leads to the initiation of DNA synthesis (see Figure 5-30).