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Gene Review

CDC6  -  cell division cycle 6

Homo sapiens

Synonyms: CDC18L, CDC6-related protein, Cdc18-related protein, Cell division control protein 6 homolog, HsCDC18, ...
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Disease relevance of CDC6


High impact information on CDC6


Biological context of CDC6

  • CDC6 is conserved during evolution and is essential and limiting for the initiation of eukaryotic DNA replication [7].
  • Although a stable mutant of CDC6 is biologically active, overexpression of this mutant or wild-type CDC6 is not sufficient to induce multiple rounds of DNA replication in the same cell cycle [7].
  • Recruitment of ORC or CDC6 to DNA is sufficient to create an artificial origin of replication in mammalian cells [8].
  • Here, we show that, in addition to being absent from nonproliferating cells, CDC6 is targeted for ubiquitin-mediated proteolysis by the anaphase promoting complex (APC)/cyclosome in G(1) [7].
  • A combination of point mutations in the destruction box and KEN-box motifs in CDC6 stabilizes the protein in G(1) and in quiescent cells [7].

Anatomical context of CDC6

  • The levels of CDC6 were relatively constant during the HeLa cell cycle [9].
  • CDC6 plays a critical role in regulation of the onset of DNA replication in eukaryotic cells [1].
  • A linear increase in MCM5 and CDC6 mRNA expression is observed in normal cervix, CIN3 and invasive cervical carcinoma [2].
  • In this study, we found that c-Myc directly bound in vivo and in vitro to the N-terminal region of human CDC6, a component of the pre-replication complex, and that both co-localized in cell nuclei [10].
  • Interestingly, cdc6 protein expression was reestablished in K562 cells that underwent endomitosis after transient or stable cyclin E overexpression [11].

Associations of CDC6 with chemical compounds


Physical interactions of CDC6

  • Cdc6 binding mirrored that of Orc2 in G(1)-arrested cells but decreased in asynchronous or M-phase cells [17].
  • We find that cyclin E binds the NH(2)-terminal region of Cdc6 containing Cy--Arg-X-Leu (RXL) motifs [18].
  • PR48 binds specifically to an amino-terminal segment of Cdc6 and forms functional holoenzyme complexes with A and C subunits of PP2A [19].
  • Mutagenesis of the two E2F binding sites on the Cdc6 promoter resulted in increased promoter activity in PC3 cells owing to elimination of the negative regulation by pRb.E2F complex but not to the level of that obtained in BPH cells [1].

Enzymatic interactions of CDC6

  • Considering recent in vitro studies, these data are consistent with a proposed model in which Cdc6 is serine-54 phosphorylated during S phase and functions as a chromatin-bound signal that prevents reformation of prereplication complexes [20].

Regulatory relationships of CDC6

  • The actions of origin recognition complex and CDC6 are suppressed through phosphorylation by cyclin-dependent kinases (Cdks) after S phase to prohibit rereplication [21].
  • The high levels of cyclin E reached in these cells appeared to influence the stabilization of cdc6 protein rather than its RNA transcription rate [11].
  • Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells [22].
  • AR may play an important role in the onset of DNA synthesis in prostate cancer cells by regulating the expression and stability of Cdc6, which is critically required for the assembly of the pre-replication complex(pre-RC) [15].
  • We demonstrate that Cdc6 expression alone is sufficient to induce a stable association of endogenous Mcm proteins with chromatin in serum-deprived cells where cyclin-dependent kinase (cdk) activity is low [23].
  • Together, these findings demonstrate an important and conserved role for Huwe1 in regulating Cdc6 abundance after DNA damage [24].
  • We also show that CDC6 expression in quiescent NHF efficiently promotes cyclin E loading onto chromatin, but it is not sufficient to activate CDK2 [25].

Other interactions of CDC6

  • The in vivo phosphorylation of CDC6 was dependent on three N-terminal CDK consensus sites, and the phosphorylation of these sites was shown to regulate the subcellular localization of CDC6 [26].
  • Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization [26].
  • Our results show that both cdt1 and cdc6 are differentially regulated during megakaryocytic differentiation and suggest an active role of cdc6 in endomitosis [11].
  • Increased transcription of MCM5 and CDC6 occurs as a consequence of cervical neoplastic progression [2].
  • The precise nucleotide of binding was identified for the two ORC and the CDC6 proteins near the start sites for leading-strand synthesis; the transition from the pre- to the post-replicative complex is accompanied by a 17 bp displacement of the ORC2 protein towards the start site [27].
  • GCN5-mediated acetylation and site-specific phosphorylation of CDC6 are both necessary for the relocalization of the protein to the cell cytoplasm in the S phase, as well as to regulate its stability [28].

Analytical, diagnostic and therapeutic context of CDC6


  1. Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer. Robles, L.D., Frost, A.R., Davila, M., Hutson, A.D., Grizzle, W.E., Chakrabarti, R. J. Biol. Chem. (2002) [Pubmed]
  2. Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. Murphy, N., Ring, M., Heffron, C.C., Martin, C.M., McGuinness, E., Sheils, O., O'Leary, J.J. Mod. Pathol. (2005) [Pubmed]
  3. Downregulation of human Cdc6 protein using a lentivirus RNA interference expression vector. Luo, F., Yee, J.K., Huang, S.H., Wu, L.T., Jong, A.Y. Methods Mol. Biol. (2006) [Pubmed]
  4. Chapter 10: New dimensions in cervical cancer screening. Cuzick, J., Mayrand, M.H., Ronco, G., Snijders, P., Wardle, J. Vaccine (2006) [Pubmed]
  5. CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Mailand, N., Diffley, J.F. Cell (2005) [Pubmed]
  6. CDKs give Cdc6 a license to drive into S phase. Ayad, N.G. Cell (2005) [Pubmed]
  7. Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. Petersen, B.O., Wagener, C., Marinoni, F., Kramer, E.R., Melixetian, M., Lazzerini Denchi, E., Gieffers, C., Matteucci, C., Peters, J.M., Helin, K. Genes Dev. (2000) [Pubmed]
  8. Recruitment of ORC or CDC6 to DNA is sufficient to create an artificial origin of replication in mammalian cells. Takeda, D.Y., Shibata, Y., Parvin, J.D., Dutta, A. Genes Dev. (2005) [Pubmed]
  9. Cell cycle regulation of human CDC6 protein. Intracellular localization, interaction with the human mcm complex, and CDC2 kinase-mediated hyperphosphorylation. Fujita, M., Yamada, C., Goto, H., Yokoyama, N., Kuzushima, K., Inagaki, M., Tsurumi, T. J. Biol. Chem. (1999) [Pubmed]
  10. CDC6 interacts with c-Myc to inhibit E-box-dependent transcription by abrogating c-Myc/Max complex. Takayama, M., Taira, T., Iguchi-Ariga, S.M., Ariga, H. FEBS Lett. (2000) [Pubmed]
  11. Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization. Bermejo, R., Vilaboa, N., Calés, C. Mol. Biol. Cell (2002) [Pubmed]
  12. p53-Dependent regulation of Cdc6 protein stability controls cellular proliferation. Duursma, A., Agami, R. Mol. Cell. Biol. (2005) [Pubmed]
  13. Caspase-3-mediated cleavage of Cdc6 induces nuclear localization of p49-truncated Cdc6 and apoptosis. Yim, H., Jin, Y.H., Park, B.D., Choi, H.J., Lee, S.K. Mol. Biol. Cell (2003) [Pubmed]
  14. Enhanced 7-ethyl-10-hydroxycamptothecin (SN-38) lethality by methylselenocysteine is associated with Chk2 phosphorylation at threonine-68 and down-regulation of Cdc6 expression. Yin, M.B., Li, Z.R., Cao, S., Durrani, F.A., Azrak, R.G., Frank, C., Rustum, Y.M. Mol. Pharmacol. (2004) [Pubmed]
  15. Androgen receptor regulates Cdc6 in synchronized LNCaP cells progressing from G1 to S phase. Bai, V.U., Cifuentes, E., Menon, M., Barrack, E.R., Reddy, G.P. J. Cell. Physiol. (2005) [Pubmed]
  16. Metazoan origin selection: origin recognition complex chromatin binding is regulated by CDC6 recruitment and ATP hydrolysis. Harvey, K.J., Newport, J. J. Biol. Chem. (2003) [Pubmed]
  17. Differential binding of replication proteins across the human c-myc replicator. Ghosh, M., Kemp, M., Liu, G., Ritzi, M., Schepers, A., Leffak, M. Mol. Cell. Biol. (2006) [Pubmed]
  18. Cyclin E uses Cdc6 as a chromatin-associated receptor required for DNA replication. Furstenthal, L., Kaiser, B.K., Swanson, C., Jackson, P.K. J. Cell Biol. (2001) [Pubmed]
  19. PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells. Yan, Z., Fedorov, S.A., Mumby, M.C., Williams, R.S. Mol. Cell. Biol. (2000) [Pubmed]
  20. Cdc6 chromatin affinity is unaffected by serine-54 phosphorylation, S-phase progression, and overexpression of cyclin A. Alexandrow, M.G., Hamlin, J.L. Mol. Cell. Biol. (2004) [Pubmed]
  21. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. Sugimoto, N., Tatsumi, Y., Tsurumi, T., Matsukage, A., Kiyono, T., Nishitani, H., Fujita, M. J. Biol. Chem. (2004) [Pubmed]
  22. Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells. Yim, H., Hwang, I.S., Choi, J.S., Chun, K.H., Jin, Y.H., Ham, Y.M., Lee, K.Y., Lee, S.K. J. Cell Biol. (2006) [Pubmed]
  23. Analysis of Cdc6 function in the assembly of mammalian prereplication complexes. Cook, J.G., Park, C.H., Burke, T.W., Leone, G., DeGregori, J., Engel, A., Nevins, J.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  24. Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. Hall, J.R., Kow, E., Nevis, K.R., Lu, C.K., Luce, K.S., Zhong, Q., Cook, J.G. Mol. Biol. Cell (2007) [Pubmed]
  25. Coordinated activation of the origin licensing factor CDC6 and CDK2 in resting human fibroblasts expressing SV40 small T antigen and cyclin E. Sotillo, E., Garriga, J., Padgaonkar, A., Kurimchak, A., Cook, J.G., Graña, X. J. Biol. Chem. (2009) [Pubmed]
  26. Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization. Petersen, B.O., Lukas, J., Sørensen, C.S., Bartek, J., Helin, K. EMBO J. (1999) [Pubmed]
  27. Localization of proteins bound to a replication origin of human DNA along the cell cycle. Abdurashidova, G., Danailov, M.B., Ochem, A., Triolo, G., Djeliova, V., Radulescu, S., Vindigni, A., Riva, S., Falaschi, A. EMBO J. (2003) [Pubmed]
  28. Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. Paolinelli, R., Mendoza-Maldonado, R., Cereseto, A., Giacca, M. Nat. Struct. Mol. Biol. (2009) [Pubmed]
  29. Improved cervical smear assessment using antibodies against proteins that regulate DNA replication. Williams, G.H., Romanowski, P., Morris, L., Madine, M., Mills, A.D., Stoeber, K., Marr, J., Laskey, R.A., Coleman, N. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  30. Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells. Yan, Z., DeGregori, J., Shohet, R., Leone, G., Stillman, B., Nevins, J.R., Williams, R.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  31. Identification and functional analysis of a human homologue of the monkey replication origin ors8. Callejo, M., Sibani, S., Di Paola, D., Price, G.G., Zannis-Hadjopoulos, M. J. Cell. Biochem. (2006) [Pubmed]
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