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Gene Review

CDC6  -  AAA family ATPase CDC6

Saccharomyces cerevisiae S288c

Synonyms: Cell division control protein 6, J0347, YJL194W
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Disease relevance of CDC6


High impact information on CDC6

  • We have cloned a Xenopus Cdc6 homolog (Xcdc6) and characterized its role in DNA replication with Xenopus egg extracts [3].
  • Here we show that Cdc6, like Sic1, also contributes to inactivation of CDKs during late mitosis in S. cerevisiae [4].
  • Deletion of the CDK-interacting domain of Cdc6 does not inhibit the function of origins of DNA replication during S phase, but instead causes a delay in mitotic exit; this delay is accentuated in the absence of Sic1 or of cyclin degradation [4].
  • Here we show that B-type CDKs in Saccharomyces cerevisiae prevent re-initiation through multiple overlapping mechanisms, including phosphorylation of the origin recognition complex (ORC), downregulation of Cdc6 activity, and nuclear exclusion of the Mcm2-7 complex [5].
  • Twenty-eight genes, including MCM2-7, CDC6, SWI4, CLN3, and a number of genes required during late M phase have been identified that are coordinately regulated by this pathway [6].

Biological context of CDC6


Anatomical context of CDC6


Associations of CDC6 with chemical compounds

  • We have used these mutants to investigate in vivo roles of the conserved lysine in the growth rate of transformant cells and the complementation of cdc6 temperature-sensitive mutant cells [12].
  • DNA sequence analysis of the CDC6 promoter revealed two sequences, 5'-C/GACGCGNC/G-3' and 5'-PuGNAGAAA-3' (where Pu is a purine, and N is any nucleotide), which are repeated three times each [13].
  • Unlike histone H2A mRNA, the CDC6 mRNA as well as CDC8 mRNA were not affected by hydroxyurea treatment [13].
  • The amino acid sequence of the 48 kDalton CDC6 gene product, as deduced from DNA sequence data, includes the three consensus peptide motifs involved in guanine nucleotide binding and GTPase activity, a target site for cAMP-dependent protein kinase and a carboxy-terminal domain related to metallothionein sequences [10].
  • In contrast, at a G2/M nocodazole arrest, Cdc6 will reload onto chromatin if and only if its CDK sites have been removed [14].

Physical interactions of CDC6

  • Indeed, Mcm7 stimulates Mcm1 binding to the early cell cycle box upstream of the promoters of MCM7 as well as CDC6 and MCM5 [15].
  • Inhibiting Cdc6 ATP hydrolysis stabilizes Cdt1 on origin DNA and prevents Mcm2-7 loading [16].
  • Strikingly, Cdc6 interacts preferentially with B-type cyclin/Cdc28 complexes and not Cln/Cdc28 in log-phase cells [17].
  • As distamycin A is a specific reagent that binds noncovalently to DNA at (A + T)-rich tracks, the stimulation of Abf1 DNA binding activity may be mediated by the Cdc6/DNA interaction [18].
  • The Cdc6 protein interacts in vivo with Cdc2 kinase complexes [19].

Enzymatic interactions of CDC6

  • Indeed, we have found that Cdc6 is ubiquitinated in vivo and degraded by a Cdc4-dependent mechanism [20].

Regulatory relationships of CDC6

  • We provide evidence that the replication defect of mcm1 mutants can be suppressed by ectopic CDC6 transcription [21].
  • Cyclin B-cdk1 kinase stimulates ORC- and Cdc6-independent steps of semiconservative plasmid replication in yeast nuclear extracts [22].
  • This inhibition requires that Clb2 be induced before Cdc6, an initiation protein required for pre-RC formation; once pre-RCs have formed, Clb2 can no longer inhibit initiation [23].
  • Saccharomyces cerevisiae Cdc6 stimulates Abf1 DNA binding activity [18].

Other interactions of CDC6

  • Our data are consistent with the notion that cells can no longer incorporate de novo synthesized Cdc6 into pre-RCs once C1b/Cdk1 kinases have been activated [24].
  • However, in cdc6 and cdc14 mutants, the mitotic loss of pDK243 with an ARS cluster was suppressed by a factor of 6-8 compared to pDK243 without the cluster [25].
  • To further investigate the molecular mechanism of nucleotide-binding function, we have demonstrated that the Cdc6 protein associates with Orc1 in vitro and in vivo [12].
  • To do this, yeast chromatin fractions from synchronized culture were prepared to detect the Mcm5 loading onto the chromatin in the presence of the wild-type Cdc6 or mutant cdc6(K114E) proteins [12].
  • Introducing a copy of the wild-type CDC6 gene into the cdc6-1 mutant strain restored the Abf1 DNA binding activity [18].

Analytical, diagnostic and therapeutic context of CDC6


  1. The Saccharomyces cerevisiae CDC6 gene is transcribed at late mitosis and encodes a ATP/GTPase controlling S phase initiation. Zwerschke, W., Rottjakob, H.W., Küntzel, H. J. Biol. Chem. (1994) [Pubmed]
  2. Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. Gonzalez, S., Klatt, P., Delgado, S., Conde, E., Lopez-Rios, F., Sanchez-Cespedes, M., Mendez, J., Antequera, F., Serrano, M. Nature (2006) [Pubmed]
  3. The Xenopus Cdc6 protein is essential for the initiation of a single round of DNA replication in cell-free extracts. Coleman, T.R., Carpenter, P.B., Dunphy, W.G. Cell (1996) [Pubmed]
  4. Cdc6 cooperates with Sic1 and Hct1 to inactivate mitotic cyclin-dependent kinases. Calzada, A., Sacristán, M., Sánchez, E., Bueno, A. Nature (2001) [Pubmed]
  5. Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nguyen, V.Q., Co, C., Li, J.J. Nature (2001) [Pubmed]
  6. Conserved homeodomain proteins interact with MADS box protein Mcm1 to restrict ECB-dependent transcription to the M/G1 phase of the cell cycle. Pramila, T., Miles, S., GuhaThakurta, D., Jemiolo, D., Breeden, L.L. Genes Dev. (2002) [Pubmed]
  7. Dual functions of CDC6: a yeast protein required for DNA replication also inhibits nuclear division. Bueno, A., Russell, P. EMBO J. (1992) [Pubmed]
  8. 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. Piatti, S., Lengauer, C., Nasmyth, K. EMBO J. (1995) [Pubmed]
  9. Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells. Kneissl, M., Pütter, V., Szalay, A.A., Grummt, F. J. Mol. Biol. (2003) [Pubmed]
  10. Cloning and characterization of the Saccharomyces cerevisiae CDC6 gene. Lisziewicz, J., Godany, A., Agoston, D.V., Küntzel, H. Nucleic Acids Res. (1988) [Pubmed]
  11. CDC6 requirement for spindle formation during maturation of mouse oocytes. Anger, M., Stein, P., Schultz, R.M. Biol. Reprod. (2005) [Pubmed]
  12. The essential role of Saccharomyces cerevisiae CDC6 nucleotide-binding site in cell growth, DNA synthesis, and Orc1 association. Wang, B., Feng, L., Hu, Y., Huang, S.H., Reynolds, C.P., Wu, L., Jong, A.Y. J. Biol. Chem. (1999) [Pubmed]
  13. CDC6 mRNA fluctuates periodically in the yeast cell cycle. Zhou, C., Jong, A. J. Biol. Chem. (1990) [Pubmed]
  14. Roles of the CDK Phosphorylation Sites of Yeast Cdc6 in Chromatin Binding and Rereplication. Honey, S., Futcher, B. Mol. Biol. Cell (2007) [Pubmed]
  15. Mcm7, a subunit of the presumptive MCM helicase, modulates its own expression in conjunction with Mcm1. Fitch, M.J., Donato, J.J., Tye, B.K. J. Biol. Chem. (2003) [Pubmed]
  16. Sequential ATP hydrolysis by Cdc6 and ORC directs loading of the Mcm2-7 helicase. Randell, J.C., Bowers, J.L., Rodríguez, H.K., Bell, S.P. Mol. Cell (2006) [Pubmed]
  17. Interaction between yeast Cdc6 protein and B-type cyclin/Cdc28 kinases. Elsasser, S., Lou, F., Wang, B., Campbell, J.L., Jong, A. Mol. Biol. Cell (1996) [Pubmed]
  18. Saccharomyces cerevisiae Cdc6 stimulates Abf1 DNA binding activity. Feng, L., Wang, B., Jong, A. J. Biol. Chem. (1998) [Pubmed]
  19. Functionally homologous DNA replication genes in fission and budding yeast. Sánchez, M., Calzada, A., Bueno, A. J. Cell. Sci. (1999) [Pubmed]
  20. The Cdc6 protein is ubiquitinated in vivo for proteolysis in Saccharomyces cerevisiae. Sánchez, M., Calzada, A., Bueno, A. J. Biol. Chem. (1999) [Pubmed]
  21. A novel Mcm1-dependent element in the SWI4, CLN3, CDC6, and CDC47 promoters activates M/G1-specific transcription. McInerny, C.J., Partridge, J.F., Mikesell, G.E., Creemer, D.P., Breeden, L.L. Genes Dev. (1997) [Pubmed]
  22. Cyclin B-cdk1 kinase stimulates ORC- and Cdc6-independent steps of semiconservative plasmid replication in yeast nuclear extracts. Duncker, B.P., Pasero, P., Braguglia, D., Heun, P., Weinreich, M., Gasser, S.M. Mol. Cell. Biol. (1999) [Pubmed]
  23. Ectopic induction of Clb2 in early G1 phase is sufficient to block prereplicative complex formation in Saccharomyces cerevisiae. Detweiler, C.S., Li, J.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  24. Activation of S-phase-promoting CDKs in late G1 defines a "point of no return" after which Cdc6 synthesis cannot promote DNA replication in yeast. Piatti, S., Böhm, T., Cocker, J.H., Diffley, J.F., Nasmyth, K. Genes Dev. (1996) [Pubmed]
  25. Addition of extra origins of replication to a minichromosome suppresses its mitotic loss in cdc6 and cdc14 mutants of Saccharomyces cerevisiae. Hogan, E., Koshland, D. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  26. Molecular cloning of Saccharomyces cerevisiae CDC6 gene. Isolation, identification, and sequence analysis. Zhou, C., Huang, S.H., Jong, A.Y. J. Biol. Chem. (1989) [Pubmed]
  27. Interaction between HP1alpha and replication proteins in mammalian cells. Auth, T., Kunkel, E., Grummt, F. Exp. Cell Res. (2006) [Pubmed]
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