BACKGROUND The initiation of DNA replication in mammalian cells is a highly coordinated process that ensures duplication of the genome only once per cell division cycle. Origins of replication are dispersed throughout the genome, and their activities are regulated via the sequential binding of pre-replication and replication factors. The origin recognition complex (ORC) is thought to be bound to chromatin throughout the cell cycle (1, 2). The pre-replication complex (Pre-RC) forms in late mitosis/early G1 phase beginning with the binding of cdt1 and cdc6 to the origin, which allows binding of the heterohexameric MCM2-7 complex. The MCM complex is thought to be the replicative helicase, and formation of the pre-RC is referred to as chromatin licensing. Subsequent initiation of DNA replication requires the activation of the S-phase promoting kinases cdk2 and cdc7. Cdc7, which is active only in complex with its regulatory subunit dbf4, phosphorylates MCM proteins bound to chromatin and allows binding of the replication factor cdc45 and DNA polymerase (3,4).The import of cdc7 to the nucleus is regulated by importin-β (5) and its binding to the origin of replication is dependent on the regulation of its localization via three domains, a nuclear localization sequence (NLS), a nuclear retention sequence (NRS) and a nuclear export sequence (NES) (6).Expression of cdc7 and dbf4 has been shown to be increased in human cancer cell lines and tissue (7); a chemical inhibitor of cdc7 blocks initiation of DNA replication and causes apoptosis in cancer cells (8).Cdc7 is also involved in activating ATR/Chk1 in response to DNA damage (9,10).
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10. Kim, J.M. et al. (2008) Oncogene 27, 3475-82.
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