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Perhaps the two most fundamental rules in DNA replication say firstly to replicate the entire genome without leaving even small parts unreplicated and secondly, not to replicate any part, even a small one, more than just once during each cell cycle. In light of the size of an average eukaryotic genome and the time of S-phase, this is an enormous challenge. If in a gedankenexperiment a mammalian cell were scaled up to the size of a football and its DNA proportionally expanded in length, the DNA would span more than the distance from the earth to the sun more than 1700 millions of kilometers in a football that has to be replicated in approximately eight hours. In contrast to a (small) bacterial genome on a single chromosome, the replication of an eukaryotic genome (portioned in several chromosomes) has to start from multiple starting points, called origins of replication, in order to be accomplished in a reasonable time. Around 30.000 such origins are activated in an average mamalian cell and give rise to replication forks in each S-phase. In order to hold the fundamental rules of once per cell cycle replication, this complexity demands an extremely sophisticated regulation of replication initiation events. The formation of the pre-replication complex (pre-RC) on potential orgins of replication at a time different from active replication is a key step in this regulation. Through the formation of the pre-RC, the replicative helicase, the MCM2-7 complex, is loaded onto chromatin. The activity of this helicase separates the DNA double strand at the beginning and during S-phase and permits access of the polymerase machinery to the template strands. In addition, only the presence of the pre-RC proteins on chromatin permits the recruitment of other proteins that are necessary to load the polymerases. Therefore, in order to avoid that replication can start more than once per cell cycle at the same site, which would lead to rereplication, the formation of the pre-RC is restricted to a period with low S-phase kinase activity, that is, at the exit from mitosis and in G1. This system normally assures the once-per cell cycle replication: The license to start replication can only be given before replication itself has started. The cell only has to safeguard in addition that a pre-RC that once gave rise to a replication fork is by this action deactivated for the remaining cell cycle. However, this very efficient system to avoid rereplication comprises on the other hand the danger that not sufficient replication forks will be created to replicate the entire genome if the cell encounters stress situations that block replication forks or lead to DNA breaks.

Assembly and Regulation of the Pre-Replication Complex: Increasing Complexity in Sight of Diversified Function and Regulation