Cdt1 and geminin in DNA replication initiation

One of the mechanisms controlling the initiation of DNA replication is the dynamic interaction between Cdt1, which promotes assembly of the pre-replication license complex, and Geminin, which inhibits it. Specifically, Cdt1 cooperates with the cell cycle protein Cdc6 to promote loading of the minichromosome maintenance helicases (MCM) onto the chromatin-bound origin recognition complex (ORC), by directly interacting with the MCM complex, and by modulating histone acetylation and inducing chromatin unfolding. Geminin, on the other hand, prevents the loading of the MCM onto the ORC both by directly binding to Cdt1, and by modulating Cdt1 stability and activity. Protein levels of Geminin and Cdt1 are tightly regulated through the cell cycle, and the Cdt1-Geminin complex likely acts as a molecular switch that can enable or disable the firing of each origin of replication. In this review we summarize structural studies of Cdt1 and Geminin and subsequent insights into how this molecular switch may function to ensure DNA is faithfully replicated only once during S phase of each cell cycle.