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

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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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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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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