+
Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation

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

Subjects

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.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

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.

Similar content being viewed by others

References

  1. Cleveland, D.W., Mao, Y. & Sullivan, K.F. Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112, 407–421 (2003).

    Article  CAS  Google Scholar 

  2. Kabeche, L. & Compton, D.A. Cyclin A regulates kinetochore microtubules to promote faithful chromosome segregation. Nature 502, 110–113 (2013).

    Article  CAS  Google Scholar 

  3. Orthwein, A. et al. Mitosis inhibits DNA double-strand break repair to guard against telomere fusions. Science 344, 189–193 (2014).

    Article  CAS  Google Scholar 

  4. Jackson, S.P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    Article  CAS  Google Scholar 

  5. Lee, J.H. & Paull, T.T. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304, 93–96 (2004).

    Article  CAS  Google Scholar 

  6. Sun, Y. et al. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat. Cell Biol. 11, 1376–1382 (2009).

    Article  CAS  Google Scholar 

  7. Zachos, G. et al. Chk1 is required for spindle checkpoint function. Dev. Cell 12, 247–260 (2007).

    Article  CAS  Google Scholar 

  8. Petsalaki, E. & Zachos, G. Chk2 prevents mitotic exit when the majority of kinetochores are unattached. J. Cell Biol. 205, 339–356 (2014).

    Article  CAS  Google Scholar 

  9. Stolz, A. et al. The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat. Cell Biol. 12, 492–499 (2010).

    Article  CAS  Google Scholar 

  10. Cheng, Z. et al. Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response. Oncogene 27, 931–941 (2008).

    Article  CAS  Google Scholar 

  11. Coffey, K. et al. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS One 7, e45539 (2012).

    Article  CAS  Google Scholar 

  12. Ghizzoni, M. et al. 6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site. Eur. J. Med. Chem. 47, 337–344 (2012).

    Article  CAS  Google Scholar 

  13. Dou, Z. et al. Dynamic localization of Mps1 to kinetochore is essential for accurate spindle microtubule attachment. Proc. Natl. Acad. Sci. USA 112, E4546–E4555 (2015).

    Article  CAS  Google Scholar 

  14. Ji, Z., Gao, H. & Yu, H. Kinetochore attachment sensed by competitive Mps1 and microtubule binding to Ndc80C. Science 348, 1260–1264 (2015).

    Article  CAS  Google Scholar 

  15. Hiruma, Y. et al. Competition between MPS1 and microtubules at kinetochores regulates spindle checkpoint signaling. Science 348, 1264–1267 (2015).

    Article  CAS  Google Scholar 

  16. Martin-Lluesma, S., Stucke, V.M. & Nigg, E.A. Role of Hec1 in spindle checkpoint signaling and kinetochore recruitment of Mad1/Mad2. Science 297, 2267–2270 (2002).

    Article  CAS  Google Scholar 

  17. Wood, K.W. et al. Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. Proc. Natl. Acad. Sci. USA 107, 5839–5844 (2010).

    Article  CAS  Google Scholar 

  18. Carmena, M., Wheelock, M., Funabiki, H. & Earnshaw, W.C. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat. Rev. Mol. Cell Biol. 13, 789–803 (2012).

    Article  CAS  Google Scholar 

  19. Lampson, M.A., Renduchitala, K., Khodjakov, A. & Kapoor, T.M. Correcting improper chromosome-spindle attachments during cell division. Nat. Cell Biol. 6, 232–237 (2004).

    Article  CAS  Google Scholar 

  20. Posch, M. et al. Sds22 regulates aurora B activity and microtubule-kinetochore interactions at mitosis. J. Cell Biol. 191, 61–74 (2010).

    Article  CAS  Google Scholar 

  21. Zeitlin, S.G., Shelby, R.D. & Sullivan, K.F. CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis. J. Cell Biol. 155, 1147–1157 (2001).

    Article  CAS  Google Scholar 

  22. Yasui, Y. et al. Autophosphorylation of a newly identified site of Aurora-B is indispensable for cytokinesis. J. Biol. Chem. 279, 12997–13003 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Cohen, P., Klumpp, S. & Schelling, D.L. An improved procedure for identifying and quantitating protein phosphatases in mammalian tissues. FEBS Lett. 250, 596–600 (1989).

    Article  CAS  Google Scholar 

  25. Favre, B., Turowski, P. & Hemmings, B.A. Differential inhibition and posttranslational modification of protein phosphatase 1 and 2A in MCF7 cells treated with calyculin-A, okadaic acid, and tautomycin. J. Biol. Chem. 272, 13856–13863 (1997).

    Article  CAS  Google Scholar 

  26. Neumann, H., Peak-Chew, S.Y. & Chin, J.W. Genetically encoding Nɛ-acetyllysine in recombinant proteins. Nat. Chem. Biol. 4, 232–234 (2008).

    Article  CAS  Google Scholar 

  27. Neumann, H. et al. A method for genetically installing site-specific acetylation in recombinant histones defines the effects of H3 K56 acetylation. Mol. Cell 36, 153–163 (2009).

    Article  CAS  Google Scholar 

  28. Honda, R., Körner, R. & Nigg, E.A. Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis. Mol. Biol. Cell 14, 3325–3341 (2003).

    Article  CAS  Google Scholar 

  29. Ruchaud, S., Carmena, M. & Earnshaw, W.C. Chromosomal passengers: conducting cell division. Nat. Rev. Mol. Cell Biol. 8, 798–812 (2007).

    Article  CAS  Google Scholar 

  30. Lemercier, C. et al. Tip60 acetyltransferase activity is controlled by phosphorylation. J. Biol. Chem. 278, 4713–4718 (2003).

    Article  CAS  Google Scholar 

  31. Charvet, C. et al. Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53. Mol. Cell 42, 584–596 (2011).

    Article  CAS  Google Scholar 

  32. Lin, S.Y. et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336, 477–481 (2012).

    Article  CAS  Google Scholar 

  33. Skoufias, D.A., Indorato, R.L., Lacroix, F., Panopoulos, A. & Margolis, R.L. Mitosis persists in the absence of Cdk1 activity when proteolysis or protein phosphatase activity is suppressed. J. Cell Biol. 179, 671–685 (2007).

    Article  CAS  Google Scholar 

  34. Foley, E.A. & Kapoor, T.M. Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat. Rev. Mol. Cell Biol. 14, 25–37 (2013).

    Article  CAS  Google Scholar 

  35. Nijenhuis, W., Vallardi, G., Teixeira, A., Kops, G.J. & Saurin, A.T. Negative feedback at kinetochores underlies a responsive spindle checkpoint signal. Nat. Cell Biol. 16, 1257–1264 (2014).

    Article  CAS  Google Scholar 

  36. Holland, A.J. & Cleveland, D.W. Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat. Med. 18, 1630–1638 (2012).

    Article  CAS  Google Scholar 

  37. Kaidi, A. & Jackson, S.P. KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling. Nature 498, 70–74 (2013).

    Article  CAS  Google Scholar 

  38. Nishino, T. et al. CENP-T-W-S-X forms a unique centromeric chromatin structure with a histone-like fold. Cell 148, 487–501 (2012).

    Article  CAS  Google Scholar 

  39. Tao, Y. et al. The structure of the FANCM-MHF complex reveals physical features for functional assembly. Nat. Commun. 3, 782 (2012).

    Article  Google Scholar 

  40. Janssen, A., van der Burg, M., Szuhai, K., Kops, G.J. & Medema, R.H. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333, 1895–1898 (2011).

    Article  CAS  Google Scholar 

  41. Xia, P. et al. EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore-microtubule interactions in mitosis. Proc. Natl. Acad. Sci. USA 109, 16564–16569 (2012).

    Article  CAS  Google Scholar 

  42. Xiao, Y. et al. Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Reports 7, 1471–1480 (2014).

    Article  CAS  Google Scholar 

  43. Moffat, J. et al. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 124, 1283–1298 (2006).

    Article  CAS  Google Scholar 

  44. Dou, Z. et al. TTK kinase is essential for the centrosomal localization of TACC2. FEBS Lett. 572, 51–56 (2004).

    Article  CAS  Google Scholar 

  45. Liu, D. et al. Human NUF2 interacts with centromere-associated protein E and is essential for a stable spindle microtubule-kinetochore attachment. J. Biol. Chem. 282, 21415–21424 (2007).

    Article  CAS  Google Scholar 

  46. Chu, Y. et al. Aurora B kinase activation requires survivin priming phosphorylation by PLK1. J. Mol. Cell Biol. 3, 260–267 (2011).

    Article  CAS  Google Scholar 

  47. Yang, Y. et al. Phosphorylation of HsMis13 by Aurora B kinase is essential for assembly of functional kinetochore. J. Biol. Chem. 283, 26726–26736 (2008).

    Article  CAS  Google Scholar 

  48. Yao, X., Anderson, K.L. & Cleveland, D.W. The microtubule-dependent motor centromere-associated protein E (CENP-E) is an integral component of kinetochore corona fibers that link centromeres to spindle microtubules. J. Cell Biol. 139, 435–447 (1997).

    Article  CAS  Google Scholar 

  49. Ding, X. et al. Probing CENP-E function in chromosome dynamics using small molecule inhibitor syntelin. Cell Res. 20, 1386–1389 (2010).

    Article  Google Scholar 

Download references

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.).

Author information

Author notes

  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

Authors
  1. Fei Mo
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Xiaoxuan Zhuang
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Xing Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Phil Y Yao
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Bo Qin
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Zeqi Su
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Jianye Zang
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Zhiyong Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Jiancun Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Zhen Dou
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Changlin Tian
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Maikun Teng
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Liwen Niu
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Donald L Hill
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Guowei Fang
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Xia Ding
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Chuanhai Fu
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Xuebiao Yao
    View author publications

    You can also search for this author inPubMed Google Scholar

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.

Corresponding authors

Correspondence to Xing Liu or Xuebiao Yao.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results and Supplementary Figures 1–9. (PDF 9371 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.2017

Search

Advanced search

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
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载