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The role of APC/CCdh1 in replication stress and origin of genomic instability

Oncogene volume 35, pages 3062–3070 (2016)Cite this article

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Abstract

It has been proposed that the APC/CCdh1 functions as a tumor suppressor by maintaining genomic stability. However, the exact nature of genomic instability following loss of Cdh1 is unclear. Using biochemistry and live cell imaging of single cells we found that Cdh1 knockdown (kd) leads to strong nuclear stabilization of the substrates cyclin A and B and deregulated kinetics of DNA replication. Restoration of the Cdh1-dependent G2 DNA damage checkpoint did not result in G2 arrest but blocked cells in prometaphase, suggesting that these cells enter mitosis despite incomplete replication. This results in DNA double-strand breaks, anaphase bridges, cytokinesis defects and tetraploidization. Tetraploid cells are the source of supernumerary centrosomes following Cdh1-kd, leading to multipolar mitosis or centrosome clustering, in turn resulting in merotelic attachment and lagging chromosomes. Whereas some of these events cause apoptosis during mitosis, surviving cells may accumulate chromosomal aberrations.

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Acknowledgements

This work is supported by Deutsche Forschungsgemeinschaft. We thank G Ihorst for statistical advice.

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Author notes

  1. D Schnerch

    Present address: 4Present address: Biozentrum, University of Basel, Basel, Switzerland.,

  2. C Greil and J Krohs: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany

    C Greil, J Krohs, D Schnerch, M Follo, J Felthaus, M Engelhardt & R Wäsch

  2. Faculty of Biology, University of Freiburg, Freiburg, Germany

    J Krohs

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  1. C Greil
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  2. J Krohs
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Correspondence to R Wäsch.

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Greil, C., Krohs, J., Schnerch, D. et al. The role of APC/CCdh1 in replication stress and origin of genomic instability. Oncogene 35, 3062–3070 (2016). https://doi.org/10.1038/onc.2015.367

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