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Inhibition of Aurora A in response to DNA damage

Oncogene volume 25, pages 338–348 (2006)Cite this article

Abstract

Mitotic kinases are the ultimate target of pathways sensing genotoxic damage and impinging on the cell cycle machinery. Here, we provide evidence that Aurora A (AurA) was inhibited upon generation of double-strand breaks in DNA. We demonstrate that AurA was not downstream of CDK1 and that inhibition of AurA and CDK1 by DNA damage occurred independently. Using a cell line functionally deficient in Chk2, a selective Chk1 inhibitor and siRNA to Chk1, we show that DNA-damage signals were delivered to AurA through a Chk1-dependent pathway. With regard to the molecular mechanism of AurA inhibition, we found that the point mutation Ser342>Ala rendered AurA resistant to inhibition by DNA damage. By means of two distinct approaches we examined the impact of reconstitution of AurA activity in DNA-damaged cells: (i) transient expression of wild-type and Ser342>Ala mutant, but not kinase-dead, AurA led to bypass of the DNA damage block; (ii) direct transduction of highly active wt-AurA into G2 arrested cells precisely after induction of DNA damage resulted in mitotic entry. We show that the mechanism through which AurA allowed entry into mitosis was reactivation of CDK1, thus indicating that AurA plays a key role upstream of CDK1. A model depicting the possible role of AurA at the onset of mitosis and upon DNA damage is presented.

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Acknowledgements

We thank F Forcellino for having made preliminary observations, J Jiricny, P Schaer and M El-Shemerly for critical reading of the manuscript and EA Nigg for helpful suggestions. We are also indebted to S Kleiner and Y Nagamine for help and suggestions in the siRNA experiments, JL Salisbury for centrin monoclonal antibody, A Kraemer and J Lukas for CHK1 monoclonal antibody and S Hausaman, Cancer Therapy Evaluation Program, NCI, NIH, Rockville, MD, USA, for supplying UCN-01. SF is supported by a grant of the Zurich Cancer League and CP is supported by the Ligue Nationale Contre le Cancer (équipe Labéllisée).

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Authors and Affiliations

  1. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

    A Krystyniak & S Ferrari

  2. Department of Oncology, Novartis Pharmaceuticals, Basel, Switzerland

    C Garcia-Echeverria

  3. CNRS UMR6061, Cell Cycle Group, University of Rennes 1, Rennes Cedex, France

    C Prigent

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  1. A Krystyniak
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  2. C Garcia-Echeverria
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  3. C Prigent
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  4. S Ferrari
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Correspondence to S Ferrari.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Krystyniak, A., Garcia-Echeverria, C., Prigent, C. et al. Inhibition of Aurora A in response to DNA damage. Oncogene 25, 338–348 (2006). https://doi.org/10.1038/sj.onc.1209056

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