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Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin

Nature volume 450, pages 1258–1262 (2007)Cite this article

Abstract

During division of metazoan cells, the nucleus disassembles to allow chromosome segregation, and then reforms in each daughter cell. Reformation of the nucleus involves chromatin decondensation and assembly of the double-membrane nuclear envelope around the chromatin; however, regulation of the process is still poorly understood1,2. In vitro, nucleus formation requires p97 (ref. 3), a hexameric ATPase implicated in membrane fusion and ubiquitin-dependent processes4,5. However, the role and relevance of p97 in nucleus formation have remained controversial. Here we show that p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B. During mitosis, Aurora B inhibits nucleus reformation by preventing chromosome decondensation and formation of the nuclear envelope membrane. During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. These data reveal an essential pathway that regulates reformation of the nucleus after mitosis and defines ubiquitin-dependent protein extraction as a common mechanism of Cdc48/p97 activity also during nucleus formation.

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Figure 1: p97 promotes nuclear envelope formation by antagonizing the inhibitory activity of Aurora B kinase.
Figure 2: p97 binds ubiquitylated Aurora B and extracts it from chromatin.
Figure 3: p97-regulated Aurora B governs chromatin decondensation and nuclear envelope formation during exit from mitosis.
Figure 4: CDC-48/p97 regulates nucleus formation and Aurora B on chromatin in C. elegans.

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References

  1. Burke, B. & Ellenberg, J. Remodelling the walls of the nucleus. Nature Rev. Mol. Cell Biol. 3, 487–497 (2002)

    Article  CAS  Google Scholar 

  2. Hetzer, M. W., Walther, T. C. & Mattaj, I. W. Pushing the envelope: structure, function, and dynamics of the nuclear periphery. Annu. Rev. Cell Dev. Biol. 21, 347–380 (2005)

    Article  CAS  Google Scholar 

  3. Hetzer, M. et al. Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly. Nature Cell Biol. 3, 1086–1091 (2001)

    Article  CAS  Google Scholar 

  4. Ye, Y. Diverse functions with a common regulator: ubiquitin takes command of an AAA ATPase. J. Struct. Biol. 156, 29–40 (2006)

    Article  CAS  Google Scholar 

  5. Jentsch, S. & Rumpf, S. Cdc48 (p97): a “molecular gearbox” in the ubiquitin pathway? Trends Biochem. Sci. 32, 6–11 (2007)

    Article  CAS  Google Scholar 

  6. Kondo, H. et al. p47 is a cofactor for p97-mediated membrane fusion. Nature 388, 75–78 (1997)

    Article  CAS  Google Scholar 

  7. Burke, B. The nuclear envelope: filling in gaps. Nature Cell Biol. 3, E273–E274 (2001)

    Article  ADS  CAS  Google Scholar 

  8. Meusser, B., Hirsch, C., Jarosch, E. & Sommer, T. ERAD: the long road to destruction. Nature Cell Biol. 7, 766–772 (2005)

    Article  CAS  Google Scholar 

  9. Vagnarelli, P. & Earnshaw, W. C. Chromosomal passengers: the four-dimensional regulation of mitotic events. Chromosoma 113, 211–222 (2004)

    Article  Google Scholar 

  10. Vong, Q. P., Cao, K., Li, H. Y., Iglesias, P. A. & Zheng, Y. Chromosome alignment and segregation regulated by ubiquitination of survivin. Science 310, 1499–1504 (2005)

    Article  ADS  CAS  Google Scholar 

  11. Hagstrom, K. A., Holmes, V. F., Cozzarelli, N. R. & Meyer, B. J. C. elegans condensin promotes mitotic chromosome architecture, centromere organization, and sister chromatid segregation during mitosis and meiosis. Genes Dev. 16, 729–742 (2002)

    Article  CAS  Google Scholar 

  12. Kaitna, S., Pasierbek, P., Jantsch, M., Loidl, J. & Glotzer, M. The aurora B kinase AIR-2 regulates kinetochores during mitosis and is required for separation of homologous Chromosomes during meiosis. Curr. Biol. 12, 798–812 (2002)

    Article  CAS  Google Scholar 

  13. Lipp, J. J., Hirota, T., Poser, I. & Peters, J. M. Aurora B controls the association of condensin I but not condensin II with mitotic chromosomes. J. Cell Sci. 120, 1245–1255 (2007)

    Article  CAS  Google Scholar 

  14. Takemoto, A. et al. Analysis of the role of Aurora B on the chromosomal targeting of condensin I. Nucleic Acids Res. 35, 2403–2412 (2007)

    Article  CAS  Google Scholar 

  15. Hsu, J. Y. et al. Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102, 279–291 (2000)

    Article  CAS  Google Scholar 

  16. Fischle, W. et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1116–1122 (2005)

    Article  ADS  CAS  Google Scholar 

  17. Hirota, T., Lipp, J. J., Toh, B. H. & Peters, J. M. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438, 1176–1180 (2005)

    Article  ADS  CAS  Google Scholar 

  18. Kourmouli, N. et al. Dynamic associations of heterochromatin protein 1 with the nuclear envelope. EMBO J. 19, 6558–6568 (2000)

    Article  CAS  Google Scholar 

  19. Sessa, F. et al. Mechanism of Aurora B activation by INCENP and inhibition by hesperadin. Mol. Cell 18, 379–391 (2005)

    Article  CAS  Google Scholar 

  20. Hauf, S. et al. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J. Cell Biol. 161, 281–294 (2003)

    Article  CAS  Google Scholar 

  21. Sugiyama, K. et al. Aurora-B associated protein phosphatases as negative regulators of kinase activation. Oncogene 21, 3103–3111 (2002)

    Article  CAS  Google Scholar 

  22. Ye, Y., Meyer, H. H. & Rapoport, T. A. Function of the p97–Ufd1–Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J. Cell Biol. 162, 71–84 (2003)

    Article  CAS  Google Scholar 

  23. Kelly, A. E. et al. Chromosomal enrichment and activation of the aurora B pathway are coupled to spatially regulate spindle assembly. Dev. Cell 12, 31–43 (2007)

    Article  ADS  CAS  Google Scholar 

  24. Poteryaev, D., Squirrell, J. M., Campbell, J. M., White, J. G. & Spang, A. Involvement of the actin cytoskeleton and homotypic membrane fusion in ER dynamics in Caenorhabditis elegans. Mol. Biol. Cell 16, 2139–2153 (2005)

    Article  CAS  Google Scholar 

  25. Mouysset, J., Kahler, C. & Hoppe, T. A conserved role of Caenorhabditis elegans CDC-48 in ER-associated protein degradation. J. Struct. Biol. 156, 41–49 (2006)

    Article  CAS  Google Scholar 

  26. Severson, A. F., Hamill, D. R., Carter, J. C., Schumacher, J. & Bowerman, B. The aurora-related kinase AIR-2 recruits ZEN-4/CeMKLP1 to the mitotic spindle at metaphase and is required for cytokinesis. Curr. Biol. 10, 1162–1171 (2000)

    Article  CAS  Google Scholar 

  27. Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003)

    Article  ADS  CAS  Google Scholar 

  28. Meyer, H. H., Shorter, J. G., Seemann, J., Pappin, D. & Warren, G. A complex of mammalian Ufd1 and Npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J. 19, 2181–2192 (2000)

    Article  CAS  Google Scholar 

  29. Murray, A. W. Cell cycle extracts. Methods Cell Biol. 36, 581–605 (1991)

    Article  CAS  Google Scholar 

  30. Lohka, M. J. Analysis of nuclear envelope assembly using extracts of Xenopus eggs. Methods Cell Biol. 53, 367–395 (1998)

    Article  CAS  Google Scholar 

  31. Wang, Y., Satoh, A., Warren, G. & Meyer, H. H. VCIP135 acts as a deubiquitinating enzyme during p97-p47-mediated reassembly of mitotic Golgi fragments. J. Cell Biol. 164, 973–978 (2004)

    Article  CAS  Google Scholar 

  32. Audhya, A. et al. A complex containing the Sm protein CAR-1 and the RNA helicase CGH-1 is required for embryonic cytokinesis in Caenorhabditis elegans. J. Cell Biol. 171, 267–279 (2005)

    Article  CAS  Google Scholar 

  33. Yamauchi, S., Yamanaka, K. & Ogura, T. Comparative analysis of expression of two p97 homologues in Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 345, 746–753 (2006)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Y. Zheng for sharing data before publication and for the GST-survivin construct, A. Musacchio for the Aurora B/INCENP construct, K. Oegema for AIR-2 antibodies, P. Jackson for MCM3 antibodies, K. Yamanaka and T. Ogura for CDC-48 antibodies, N. Kraut (Boehringer Ingelheim, Vienna) for hesperadin, and C. Brasseur and C. Zbinden for technical help. This work was supported by grants of the Swiss National Fund, the ETH Zurich, the Bonizzi-Theler Stiftung, the Roche Research Foundations (to K.R.), the Novartis Foundation and the DAAD (to O.P.). R.B., F.M.S. and T.B. were on the Molecular Life Science PhD Program Zurich.

Author Contributions M.G. and F.M.S. performed the C. elegans experiments. H.H.M. wrote the paper. All authors discussed the results and commented on the manuscript.

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  1. Kristijan Ramadan and Roland Bruderer: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland,

    Kristijan Ramadan, Roland Bruderer, Fabio M. Spiga, Oliver Popp, Tina Baur, Monica Gotta & Hemmo H. Meyer

  2. Department of Genetic Medicine and Development, University of Geneva School of Medicine, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland,

    Fabio M. Spiga & Monica Gotta

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Correspondence to Hemmo H. Meyer.

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Ramadan, K., Bruderer, R., Spiga, F. et al. Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin. Nature 450, 1258–1262 (2007). https://doi.org/10.1038/nature06388

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