Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Cdc6 synthesis regulates replication competence in Xenopus oocytes


The early division cycles of an embryo rely on the oocyte's ability to replicate DNA. During meiosis, oocytes temporarily lose this ability. After a single round of pre-meiotic S-phase, oocytes enter meiosis and rapidly arrest at prophase of meiosis I (G2)1. Upon hormonal stimulation, arrested oocytes resume meiosis, re-establish DNA replication competence in meiosis I shortly after germinal vesicle breakdown (GVBD), but repress replication until fertilization2,3. How oocytes lose and regain replication competence during meiosis are important questions underlying the production of functional gametes. Here we show that the inability of immature Xenopus oocytes to replicate is linked to the absence of the Cdc6 protein and the cytoplasmic localization of other initiation proteins. Injection of Cdc6 protein into immature oocytes does not induce DNA replication. However, injection of Cdc6 into oocytes undergoing GVBD is sufficient to induce DNA replication in the absence of protein synthesis. Our results show that GVBD and Cdc6 synthesis are the only events that limit the establishment of the oocyte's replication competence during meiosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Xenopus immature oocytes have a defect in pre-replication complex (RC) assembly.
Figure 2: Cdc6 synthesis occurs during meiosis I after germinal vesicle breakdown (GVBD).
Figure 3: Injection of Cdc6 into maturing oocytes treated with CHX induces DNA replication.

Similar content being viewed by others


  1. Gurdon, J. B. On the origin and persistence of a cytoplasmic state inducing nuclear DNA synthesis in frogs' eggs. Proc. Natl Acad. Sci. USA 58, 545–552 (1967)

    Article  CAS  ADS  Google Scholar 

  2. Sagata, N. What does Mos do in oocytes and somatic cells? Bioessays 19, 13–21 (1997)

    Article  CAS  Google Scholar 

  3. Furuno, N. et al. Suppression of DNA replication via Mos function during meiotic divisions in Xenopus oocytes. EMBO J. 13, 2399–2410 (1994)

    Article  CAS  Google Scholar 

  4. Laskey, R. A., Harland, R. M. & Mechali, M. Induction of chromosome replication during maturation of amphibian oocytes. Ciba Found. Symp. 98, 25–43 (1983)

    CAS  PubMed  Google Scholar 

  5. Cox, L. S. & Leno, G. H. Extracts from eggs and oocytes of Xenopus laevis differ in their capacities for nuclear assembly and DNA replication. J. Cell Sci. 97 Pt 1, 177–184 (1990)

    PubMed  Google Scholar 

  6. Kelly, T. J. & Brown, G. W. Regulation of chromosome replication. Annu. Rev. Biochem. 69, 829–880 (2000)

    Article  CAS  Google Scholar 

  7. Diffley, J. F. DNA replication: building the perfect switch. Curr. Biol. 11, R367–R370 (2001)

    Article  CAS  Google Scholar 

  8. Takisawa, H., Mimura, S. & Kubota, Y. Eukaryotic DNA replication: from pre-replication complex to initiation complex. Curr. Opin. Cell Biol. 12, 690–696 (2000)

    Article  CAS  Google Scholar 

  9. Blow, J. J. Control of chromosomal DNA replication in the early Xenopus embryo. EMBO J. 20, 3293–3297 (2001)

    Article  CAS  Google Scholar 

  10. Pereverzeva, I., Whitmire, E., Khan, B. & Coue, M. Distinct phosphoisoforms of the Xenopus Mcm4 protein regulate the function of the Mcm complex. Mol. Cell Biol. 20, 3667–3676 (2000)

    Article  CAS  Google Scholar 

  11. Yang, J. et al. Control of cyclin B1 localization through regulated binding of the nuclear export factor CRM1. Genes Dev. 12, 2131–2143 (1998)

    Article  CAS  Google Scholar 

  12. Yang, J., Winkler, K., Yoshida, M. & Kornbluth, S. Maintenance of G2 arrest in the Xenopus oocyte: a role for 14-3-3-mediated inhibition of Cdc25 nuclear import. EMBO J. 18, 2174–2183 (1999)

    Article  CAS  Google Scholar 

  13. Li, J., Meyer, A. N. & Donoghue, D. J. Nuclear localization of cyclin B1 mediates its biological activity and is regulated by phosphorylation. Proc. Natl Acad. Sci. USA 94, 502–507 (1997)

    Article  CAS  ADS  Google Scholar 

  14. Labib, K., Diffley, J. F. & Kearsey, S. E. G1-phase and B-type cyclins exclude the DNA-replication factor Mcm4 from the nucleus. Nature Cell Biol. 1, 415–422 (1999)

    Article  CAS  Google Scholar 

  15. Nguyen, V. Q., Co, C., Irie, K. & Li, J. J. Clb/Cdc28 kinases promote nuclear export of the replication initiator proteins Mcm2-7. Curr. Biol. 10, 195–205 (2000)

    Article  CAS  Google Scholar 

  16. Swenson, K. I., Farrell, K. M. & Ruderman, J. V. The clam embryo protein cyclin A induces entry into M phase and the resumption of meiosis in Xenopus oocytes. Cell 47, 861–870 (1986)

    Article  CAS  Google Scholar 

  17. Roy, L. M. et al. Activation of p34cdc2 kinase by cyclin A. J. Cell Biol. 113, 507–514 (1991)

    Article  CAS  Google Scholar 

  18. Sato, N., Arai, K. & Masai, H. Human and Xenopus cDNAs encoding budding yeast Cdc7-related kinases: in vitro phosphorylation of MCM subunits by a putative human homologue of Cdc7. EMBO J. 16, 4340–4351 (1997)

    Article  CAS  Google Scholar 

  19. Jiang, W. & Hunter, T. Identification and characterization of a human protein kinase related to budding yeast Cdc7p. Proc. Natl Acad. Sci. USA 94, 14320–14325 (1997)

    Article  CAS  ADS  Google Scholar 

  20. Leno, G. H. & Laskey, R. A. DNA replication in cell-free extracts from Xenopus laevis. Methods Cell Biol. 36, 561–579 (1991)

    Article  CAS  Google Scholar 

  21. Coleman, T. R., Carpenter, P. B. & Dunphy, W. G. The Xenopus Cdc6 protein is essential for the initiation of a single round of DNA replication in cell-free extracts. Cell 87, 53–63 (1996)

    Article  CAS  Google Scholar 

  22. Mimura, S. & Takisawa, H. Xenopus Cdc45-dependent loading of DNA polymerase alpha onto chromatin under the control of S-phase Cdk. EMBO J. 17, 5699–5707 (1998)

    Article  CAS  Google Scholar 

  23. Findeisen, M., El-Denary, M., Kapitza, T., Graf, R. & Strausfeld, U. Cyclin A-dependent kinase activity affects chromatin binding of ORC, Cdc6, and MCM in egg extracts of Xenopus laevis. Eur. J. Biochem. 264, 415–426 (1999)

    Article  CAS  Google Scholar 

  24. Natale, D. A., Li, C. J., Sun, W. H. & DePamphilis, M. L. Selective instability of ORC1 protein accounts for the absence of functional origin recognition complexes during the M-G(1) transition in mammals. EMBO J. 19, 2728–2738 (2000)

    Article  CAS  Google Scholar 

  25. Todorov, I. T., Attaran, A. & Kearsey, S. E. BM28, a human member of the MCM2-3-5 family, is displaced from chromatin during DNA replication. J. Cell Biol. 129, 1433–1445 (1995)

    Article  CAS  Google Scholar 

  26. Madine, M. A., Khoo, C. Y., Mills, A. D. & Laskey, R. A. MCM3 complex required for cell cycle regulation of DNA replication in vertebrate cells. Nature 375, 421–424 (1995)

    Article  CAS  ADS  Google Scholar 

  27. Kubota, Y. et al. Licensing of DNA replication by a multi-protein complex of MCM/P1 proteins in Xenopus eggs. EMBO J. 16, 3320–3331 (1997)

    Article  CAS  Google Scholar 

  28. Lemaître, J. M., Bocquet, S. & Méchali, M. Competence to replicate in the unfertilized egg is conferred by Cdc6 during meiotic maturation. Nature 419, 718–722 (2002)

    Article  ADS  Google Scholar 

  29. Fisher, D., Coux, O., Bompard-Marechal, G. & Doree, M. Germinal vesicle material is dispensable for oscillations in cdc2 and MAP kinase activities, cyclin B degradation and synthesis during meiosis in Xenopus oocytes. Biol. Cell 90, 497–508 (1998)

    Article  CAS  Google Scholar 

Download references


We thank M. DePamphilis, M. Doree, W. Dunphy, T. Hunt, U. Strausfeld, H. Takisawa, I. Todorov and M. Yoshida for providing reagents and C. MacDonald, C. Pfarr, B. Schneider and S. Ravnik for critical reading of the manuscript. This work was supported by grants from the American Heart Association, South Plains Foundation and the NIH (to M.C.). E.W. was supported by a NIH training grant.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Martine Coué.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Whitmire, E., Khan, B. & Coué, M. Cdc6 synthesis regulates replication competence in Xenopus oocytes. Nature 419, 722–725 (2002).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing