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The CHK2–BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells

Nature Cell Biology volume 12, pages 492–499 (2010)Cite this article

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Abstract

Chromosomal instability (CIN) is a major hallmark of human cancer and might contribute to tumorigenesis1. Genes required for the normal progression of mitosis represent potential CIN genes and, as such, are important tumour suppressors. The Chk2 kinase and its downstream targets p53 and Brca1 are tumour suppressors that have been functionally linked to the DNA damage response pathway2. Here, we report a function of Chk2, independent of p53 and DNA damage, that is required for proper progression of mitosis, and for the maintenance of chromosomal stability in human somatic cells. Depletion of Chk2 or abrogation of its kinase activity causes abnormal mitotic spindle assembly associated with a delay in mitosis, which promotes the generation of lagging chromosomes, chromosome missegregation and CIN, while still allowing survival and growth. Furthermore, we have identified Brca1 as a mitotic target of the Chk2 kinase in the absence of DNA damage. Accordingly, loss of BRCA1 or its Chk2-mediated phosphorylation leads to spindle formation defects and CIN. Thus, the CHK2–BRCA1 tumour suppressor pathway is required for chromosomal stability, which might contribute to their tumour suppressor function.

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Figure 1: CHK2 is required for chromosomal stability.
Figure 2: Chk2 is required for timely progression of mitosis.
Figure 3: Chk2 is required for normal mitotic spindle assembly.
Figure 4: Loss of CHK2 results in mal-oriented lagging chromosomes that are suppressed by MCAK expression.
Figure 5: Chk2-mediated Brca1 phosphorylation is required for mitotic spindle formation and chromosomal stability.

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Acknowledgements

We thank Robert Benezra, Loren Michel, Prasad Jallepalli, Bert Vogelstein, Jiri Lukas, Stephen Taylor, Reuven Agami, Fen Xia, Junjie Chen, Sylvie Mazoyer, Jay Chung, Michael Brandeis, Linda Wordeman and Duane Compton for providing cell lines, antibodies and plasmids. We thank Robert J. Schultz (Developmental Therapeutics Program of the National Cancer Institute, USA) for the gift of UCN-01, and Rolf Müller and Alexandra Elli for support. We are grateful to Heike Krebber and Matthias Dobbelstein for comments on the manuscript. This work was supported by a grant and a Heisenberg fellowship to H.B. from the Deutsche Forschungsgemeinschaft.

Author information

Author notes

  1. Wilko Weichert

    Present address: Ruprecht-Karls-University Heidelberg, Institute of Pathology, Im Neuenheimer Feld 220/221, Heidelberg, D-69120, Germany

  2. Celia Vogel

    Present address: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.,

  3. Ailine Stolz and Norman Ertych: These authors contributed equally to this work.

Authors and Affiliations

  1. Philipps University Marburg, Institute for Molecular Biology and Tumour Research (IMT), Emil-Mannkopf-Strasse 2, Marburg, D-35037, Germany

    Ailine Stolz, Norman Ertych, Anne Kienitz, Celia Vogel, Verena Schneider & Holger Bastians

  2. Philipps University Marburg, Institute of Human Genetics, Bahnhofstrasse 7, Marburg, D-35033, Germany

    Barbara Fritz

  3. Philipps University Marburg, Institute of Cell Biology and Cell Pathology, Robert-Koch-Strasse 6, Marburg, D-35032, Germany

    Ralf Jacob

  4. Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin, D-13125, Germany

    Gunnar Dittmar

  5. Charite University Hospital, Institute of Pathology, Chariteplatz 1, Berlin, D-10117, Germany

    Wilko Weichert

  6. Friedrich-Schiller-University Jena, Institute of Pathology, Ziegelmühlenweng 1, Jena, D-07740, Germany

    Iver Petersen

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Contributions

A.S., N.E., A.K., C.V. and V.S. performed and analysed most experiments; B.F. performed the M-FISH experiments; R.J. supported the live-cell analyses; G.D. performed the MRM analyses; W.W. and I.P. performed and analysed the immunohistochemisty on human tumour samples; H.B. designed and coordinated the study, performed experiments, analysed data and wrote the manuscript. All authors discussed the work and commented on the manuscript.

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Correspondence to Holger Bastians.

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The authors declare no competing financial interests.

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Stolz, A., Ertych, N., Kienitz, A. et al. The CHK2–BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat Cell Biol 12, 492–499 (2010). https://doi.org/10.1038/ncb2051

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