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p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

Oncogene volume 29, pages 3477–3489 (2010)Cite this article

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Abstract

The long-term cellular response to DNA damage is controlled by the tumor suppressor p53. It results in cell-cycle arrest followed by DNA repair and, depending on the degree of damage inflicted, premature senescence or apoptotic cell death. Here we show that in normal diploid fibroblasts the ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C)–Cdh1 becomes prematurely activated in G2 as part of the sustained long-term but not the rapid short-term response to genotoxic stress and results in the degradation of numerous APC/C substrates. Using HCT116 somatic knockout cells we show that mechanistically premature APC/C activation depends on p53 and its transcriptional target p21 that mediates the signal through downregulation of the APC/C inhibitor Emi1. Cdc14B is dispensable in this setting but might function redundantly. Our data suggest an unexpected role for the APC/C in executing a part of the p53-dependent DNA damage response that leads to premature senescence.

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Acknowledgements

We thank Eli Berdougo, Philipp Haemmati, Christoph Hanski, Hans-Jürgen Heidebrecht, Prasad Jallepalli, Bert Vogelstein and Ralph Wäsch for the generous supply of reagents. We acknowledge Matthias Truss for help with lentivirus production and Ralf Uecker for excellent technical assistance. This work was supported by Grants HA1575/2-1 and WI2043/2-2 from the Deutsche Forschungsgemeinschaft (DFG).

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  1. Children's Hospital, Laboratory for Molecular Biology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    L Wiebusch & C Hagemeier

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  1. L Wiebusch
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Correspondence to L Wiebusch.

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Wiebusch, L., Hagemeier, C. p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress. Oncogene 29, 3477–3489 (2010). https://doi.org/10.1038/onc.2010.99

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