CDC6 association with the ORC:origin complex

Stable Identifier
R-HSA-68689
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Pathway
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Homo sapiens
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Cdc6 is a regulator of DNA replication initiation in both yeasts and human cells (Mendez and Stillman 2000), but its mechanism of action differs between the two systems. Genetic studies in budding yeast (S. cerevisiae) and fission yeast (S. pombe) indicate that the normal function of Cdc6 protein is required to restrict DNA replication to once per cell cycle. Specifically, Cdc6 may function as an ATPase switch linked to Mcm2-7:Cdt1 association with the Cdc6:ORC:origin complex (Lee and Bell 2000). In S. cerevisiae, Cdc6 protein is expressed late in the M phase of the cell cycle and, in cells with a prolonged G1 phase, late in G1. This protein has a short half-life, and is destroyed by ubiquitin-mediated proteolysis, mediated by the SCF complex (Piatti et al. 1995, Drury et al. 1997, Drury et al. 2000, Perkins et al. 2001). Human Cdc6 protein levels are reduced early in G1 but otherwise are constant throughout the cell cycle (Petersen et al. 2000). Some reports have suggested that after cells enter S phase, Cdc6 is phosphorylated, excluded from the nucleus and subject to ubiquitination and degradation (Saha et al. 1998, Jiang et al. 1999, Petersen et al. 1999). Replenishing Cdc6 protein levels during G1 appears to be regulated by E2F transcription factors (Yan et al. 1998).

Literature References
PubMed ID Title Journal Year
9566895 Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase.

Thome, KC, Hou, ZH, Saha, P, Dutta, A, Hendricks, M, Parvin, JD, Chen, J, Lawlis, SJ

Mol Cell Biol 1998
10712901 The cyclin-dependent kinase Cdc28p regulates distinct modes of Cdc6p proteolysis during the budding yeast cell cycle.

Diffley, JF, Drury, LS, Perkins, G

Curr Biol 2000
11532947 Separate SCF(CDC4) recognition elements target Cdc6 for proteolysis in S phase and mitosis.

Diffley, JF, Drury, LS, Perkins, G

EMBO J 2001
10339564 Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6.

Jiang, W, Wells, NJ, Hunter, T

Proc Natl Acad Sci U S A 1999
11046155 Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis.

Mendez, J, Stillman, B

Mol Cell Biol 2000
9520412 Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.

Leone, G, Williams, RS, Nevins, JR, DeGregori, J, Stillman, B, Shohet, R, Yan, Z

Proc Natl Acad Sci U S A 1998
10995389 Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1.

Petersen, BO, Wagener, C, Kramer, ER, Peters, JM, Helin, K, Gieffers, C, Matteucci, C, Melixetian, M, Marinoni, F, Denchi, EL

Genes Dev 2000
9312054 The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast.

Diffley, JF, Drury, LS, Perkins, G

EMBO J 1997
9889196 Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization.

Petersen, BO, Helin, K, Sørensen, CS, Lukas, J

EMBO J 1999
10801458 ATPase switches controlling DNA replication initiation.

Bell, SP, Lee, DG

Curr Opin Cell Biol 2000
7641697 Cdc6 is an unstable protein whose de novo synthesis in G1 is important for the onset of S phase and for preventing a 'reductional' anaphase in the budding yeast Saccharomyces cerevisiae.

Nasmyth, K, Piatti, S, Lengauer, C

EMBO J 1995
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