Mechanism of Mcm2-7 Loading

The head-to-head arrangement of Mcm2-7 in the double-hexamer provides a molecular basis for the establishment of bi-directional DNA replication forks at an origin. But how are two Mcm2-7 hexamers loaded cooperatively, yet in opposite orientation by one set of loading factors?

Mechanism and Regulation of Origin Activation

Strikingly, in eukaryotes, the replicative helicase comprises six distinct essential subunits (Mcm2-7), and helicase loading and activation are strictly consecutive events that require a complex cascade of accessory factors. While the tight regulation of helicase activation during origin firing allows the cell to coordinate DNA replication with other cell cycle processes such as chromosome segregation and cell division, it is not understood why so many additional factors are required to activate the eukaryotic helicase and to direct the formation of the replication forks, and why the helicase itself is a hetero-hexameric (or double-hexameric) assembly.