Fig. 6. Three ways out of the cell cycle. The replication initiation factors ORC, Cdc6 and MCM are present throughout all phases of the proliferative cell cycle. In contrast, the Cdc6 and MCM components of the replication initiation pathway are downregulated in quiescent, terminally differentiated and replicative senescent ‘out-of-cycle’ states. Thus, Cdc6 and MCM proteins comply with the theoretical definition of a proliferation marker.