Cell Cycle / Checkpoint Control

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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 prereplication and replication factors. The origin recognition complex (ORC) is thought to be bound to chromatin throughout the cell cycle (1,2). The prereplication 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).Binding of CDT1 to geminin prevents pre-RC formation, and expression and degradation of geminin serve to regulate CDT1 activity (reviewed in 5). The interaction of CDT1 with MCM proteins is important in pre-RC formation and licensing (6,7). Both cdc6 and CDT1 are degraded by the ubiquitin proteasome pathway in response to DNA damage associated with rereplication (8).

1. Okuno, Y. et al. (2001) EMBO J 20, 4263-77.
2. McNairn, A.J. et al. (2005) Exp Cell Res 308, 345-56.
3. Bell, S.P. and Dutta, A. (2002) Annu Rev Biochem 71, 333-74.
4. Tsuji, T. et al. (2006) Mol Biol Cell 17, 4459-72.
5. Tada, S. (2007) Front Biosci 12, 1629-41.
6. You, Z. and Masai, H. (2008) J Biol Chem 283, 24469-77.
7. Teer, J.K. and Dutta, A. (2008) J Biol Chem 283, 6817-25.
8. Hall, J.R. et al. (2008) J Biol Chem 283, 25356-63.

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CDT1 Antibody

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