The ORC/Cdc6/MCM2–7 complex, a new power player for regulated helicase loading

The regulated loading of the replicative helicase MCM2–7 onto DNA is central to DNA replication. Errors during this process lead to genetic disorders, like Meier-Gorlin syndrome, or to genomic instability and cancer. Analyzing DNA replication will allow us to understand how helicase loading is misregulated in disease and will promote the development of diagnostic tools and therapeutics that target DNA replication proteins. The MCM2–7 helicase is a heterohexamer, and its subunits form a ringshaped structure. Helicase loading onto DNA, also termed pre-replicative complex (pre-RC) formation, is facilitated by the six-subunit origin recognition complex (ORC), cell-division-cycle 6 (Cdc6), and Cdc10 protein-dependent transcript 1 (Cdt1). These proteins can open the MCM2–7 ring and load two MCM2–7 hexamers into a head-to-head doublehexamer around double-stranded DNA. Helicase loading is an energy-consuming process and requires ATP hydrolysis by Cdc6. During late M-phase, Cdc6 binds to ORC, and then the ORC/Cdc6 complex is competent for pre-RC formation. Equally, MCM2–7 forms a tight complex with Cdt1, which is required in budding yeast for nuclear import of the MCM2–7 helicase. Furthermore, a specific Cdt1MCM2–7 interaction involving the Cdt1and Mcm6 C-terminal domains has been characterized in budding yeast and higher eukaryotes, and this interaction could be important for pre-RC formation. The question of how Cdt1 recruits MCM2–7 toward ORC/Cdc6 has recently been under intense scrutiny. Takara et al. showed that the Cdt1 C terminus is The ORC/Cdc6/MCM2–7 complex, a new power player for regulated helicase loading