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Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation

Nature Chemical Biology volume 12, pages 226–232 (2016)Cite this article

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Abstract

Faithful segregation of chromosomes in mammalian cells requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying cyclin-dependent kinase 1 (CDK1) activation, which triggers mitotic entry, have been extensively studied, the regulatory mechanisms that couple CDK1–cyclin B activity to chromosome stability are not well understood. Here, we identified a signaling axis in which Aurora B activity is modulated by CDK1–cyclin B via the acetyltransferase TIP60 in human cell division. CDK1–cyclin B phosphorylates Ser90 of TIP60, which elicits TIP60-dependent acetylation of Aurora B and promotes accurate chromosome segregation in mitosis. Mechanistically, TIP60 acetylation of Aurora B at Lys215 protects Aurora B's activation loop from dephosphorylation by the phosphatase PP2A to ensure a robust, error-free metaphase-anaphase transition. These findings delineate a conserved signaling cascade that integrates protein phosphorylation and acetylation with cell cycle progression for maintenance of genomic stability.

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Figure 1: Accurate chromosome segregation in mitosis requires TIP60 acetyltransferase activity.
Figure 2: TIP60 localizes to kinetochores and orchestrates accurate kinetochore-microtubule attachments.
Figure 3: Acetylation of Aurora B by TIP60 promotes Aurora B kinase activity and attachment error correction.
Figure 4: Acetylation of Aurora B by TIP60 antagonizes dephosphorylation of Thr232 by PP2A.
Figure 5: Phosphorylation of TIP60 by CDK1 promotes Aurora B activity for error-free chromosome segregation.

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Acknowledgements

We are grateful to Y. Shi (University of Science & Technology of China) and Y. Chen (Natural Science Foundation of China) for support; to S. Zhao (Fudan University) for mass spectrometric assistance; and to J. Chin (MRC Laboratory of Molecular Biology, Cambridge, UK) for reagents. This work was supported in part by the Natural Science Foundation of China (grants 31430054, 31320103904 and 91313303, 2002CB713700 to X.Y.; 31501095 to X.L.; 81270466 to X.D.; 31371363 to Z.D.; 31271439 to C.F.; and 91213303 to Z.W.), 973 projects (2014CB964803 to X.Y.; 2012CB917200 to J.Za., L.N.; 2012CB945002, 2013CB911203 to Z.D.; 2002CB713701 to C.F.); MOE Innovative team IRT13038, Fundamental Research Funds for the Central Universities WK2070000066; Chinese Academy of Sciences Center of Excellence 2015HSC-UE010; and the US National Institutes of Health (DK56292 and CA164133 to X.Y.).

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  1. Fei Mo and Xiaoxuan Zhuang: These authors contributed equally to this work.

Authors and Affiliations

  1. Anhui Key Laboratory for Cellular Dynamics & Chemical Biology, Hefei, China

    Fei Mo, Xiaoxuan Zhuang, Xing Liu, Bo Qin, Jianye Zang, Zhiyong Wang, Jiancun Zhang, Zhen Dou, Changlin Tian, Maikun Teng, Liwen Niu, Guowei Fang, Chuanhai Fu & Xuebiao Yao

  2. Laboratory for Organelle Dynamics & Plasticity Control, University of Science & Technology of China School of Life Sciences, Hefei, China

    Fei Mo, Xiaoxuan Zhuang, Xing Liu, Bo Qin, Jianye Zang, Zhiyong Wang, Jiancun Zhang, Zhen Dou, Changlin Tian, Maikun Teng, Liwen Niu, Guowei Fang, Chuanhai Fu & Xuebiao Yao

  3. Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Hefei, China

    Xing Liu, Jianye Zang, Zhiyong Wang, Zhen Dou, Changlin Tian, Maikun Teng, Liwen Niu, Chuanhai Fu & Xuebiao Yao

  4. Hefei National Laboratory for Physical Sciences at Nanoscale, Hefei, China

    Xing Liu, Jianye Zang, Zhiyong Wang, Zhen Dou, Changlin Tian, Maikun Teng, Liwen Niu, Chuanhai Fu & Xuebiao Yao

  5. Molecular Imaging Center, Morehouse School of Medicine, Atlanta, Georgia, USA

    Xing Liu, Phil Y Yao, Bo Qin, Zeqi Su & Xia Ding

  6. Department of Medical Cell Biology, Beijing University of Chinese Medicine, Beijing, China

    Zeqi Su & Xia Ding

  7. State Key Laboratory of Respiratory Diseases, Guangzhou, China

    Jiancun Zhang

  8. Comprehensive Cancer Center, University of Alabama, Birmingham, Alabama, USA

    Donald L Hill

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Contributions

X.Y. and G.F. conceived the project. F.M., X.Z. and X.L. designed and performed most biochemical and cell biological experiments. P.Y.Y., B.Q., Z.S., J.Za., Z.W. and J.Zh. performed chemical biological experiments and evaluated small molecule inhibitors. Z.D., C.T., M.T., L.N. and C.F. assisted in recombinant protein engineering and purification. F.M., X.Z., X.L., P.Y.Y., B.Q., Z.S., J.Za., C.F. and X.D. performed data analyses. F.M., X.Z., X.L. and X.Y. wrote the manuscript. D.L.H. and G.F. edited the manuscript.

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Correspondence to Xing Liu or Xuebiao Yao.

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Mo, F., Zhuang, X., Liu, X. et al. Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation. Nat Chem Biol 12, 226–232 (2016). https://doi.org/10.1038/nchembio.2017

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