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Phosphorylation of the CPC by Cdk1 promotes chromosome bi-orientation

Nature volume 467, pages 719–723 (2010)Cite this article

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Abstract

Successful partition of replicated genomes at cell division requires chromosome attachment to opposite poles of mitotic spindle (bi-orientation). Any defects in this regulation bring about chromosomal instability, which may accelerate tumour progression in humans. To achieve chromosome bi-orientation at prometaphase, the chromosomal passenger complex (CPC), composed of catalytic kinase Aurora B and regulatory components (INCENP, Survivin and Borealin), must be localized to centromeres to phosphorylate kinetochore substrates1,2,3,4,5,6,7. Although the CPC dynamically changes the subcellular localization, the regulation of centromere targeting is largely unknown1. Here we isolated a fission yeast cyclin B mutant defective specifically in chromosome bi-orientation. Accordingly, we identified Cdk1 (also known as Cdc2)–cyclin-B-dependent phosphorylation of Survivin. Preventing Survivin phosphorylation impairs centromere CPC targeting as well as chromosome bi-orientation, whereas phosphomimetic Survivin suppresses the bi-orientation defect in the cyclin B mutant. Survivin phosphorylation promotes direct binding with shugoshin8,9, which we now define as a conserved centromeric adaptor of the CPC. In human cells, the phosphorylation of Borealin has a comparable role. Thus, our study resolves the conserved mechanisms of CPC targeting to centromeres, highlighting a key role of Cdk1–cyclin B in chromosome bi-orientation.

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Figure 1: Cdk1–cyclin B has a role in chromosome bi-orientation by phosphorylating Bir1.
Figure 2: Phosphorylation of Bir1 promotes the association with Sgo2 and targeting the CPC to centromeres.
Figure 3: Phosphorylation of Borealin by Cdk1 promotes the association with shugoshins and centromere targeting of the CPC in human cells.
Figure 4: Fission yeast Survivin and human Borealin have comparable roles in binding with shugoshin and CPC targeting.

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Acknowledgements

We thank S. Hauf for critically reading the manuscript and the Yeast Genetic Resource Center (YGRC) for yeast strains, and all the members of our laboratory, particularly S. A. Kawashima, for their valuable support and discussion. This work was supported in part by Global COE Program (Integrative Life Science Based on the Study of Biosignaling Mechanisms), JSPS Research Fellowship (to T.T. and Y.T.) and a Grant-in-Aid for Specially Promoted Research, MEXT, Japan (to Y.W.).

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Authors and Affiliations

  1. Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Tokyo 113-0032, Japan ,

    Tatsuya Tsukahara, Yuji Tanno & Yoshinori Watanabe

  2. Graduate Program in Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Yayoi, Tokyo 113-0032, Japan ,

    Tatsuya Tsukahara & Yoshinori Watanabe

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Contributions

Most experiments were performed by T.T. except those in Fig. 3a and Supplementary Fig. 11, which were performed by Y.T. Experimental design and interpretation of data were conducted by all authors. Y.W. supervised the project, and T.T. and Y.W. wrote the paper.

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Correspondence to Yoshinori Watanabe.

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The authors declare no competing financial interests.

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Tsukahara, T., Tanno, Y. & Watanabe, Y. Phosphorylation of the CPC by Cdk1 promotes chromosome bi-orientation. Nature 467, 719–723 (2010). https://doi.org/10.1038/nature09390

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