Cell cycle regulation of DNA replication initiation proteins in mammalian cells

Genomic DNA has to be replicated completely and only once during a single cell cycle in order to maintain integrity. Eukaryotes have developed highly regulated machinery for precisely replicating genomic DNA that is fragmented into multiple chromosomes. Our knowledge of such mechanisms largely depends on findings with budding yeast, since identification of specific DNA sequences acting as replication origins, autonomously replicating sequences, has allowed extensive analyses of the initiation of DNA replication. Several factors essential for regulation of initiation have been identified, including ORC, CDC6 and MCM. Subsequent work has suggested that the fundamental machinery for DNA replication may be conserved in metazoan embryonic cells in which replication occurs sequence-independently, and also in mammalian nonembryonic cells, where replication origins are more specific. However, there are specific differences. In this review, information on function and regulation of mammalian initiation factors, ORC, CDC6 and MCM, is summarized, and yeast and embryonic systems are compared. A hypothetical model for the state of prereplication chromatin in mammalian cell nuclei and regulation during the cell cycle is also proposed.