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The ubiquitin ligase APCCdh1 is required to maintain genome integrity in primary human cells

Oncogene volume 27, pages 907–917 (2008)Cite this article

Abstract

Ensuring precise DNA replication and chromosome segregation is essential during cell division in order to provide genomic stability and avoid malignant growth. Proteolytic control of cell cycle regulators by the anaphase-promoting complex, activated by Cdh1 (APCCdh1), is responsible for a stable G1 phase after mitotic exit allowing accurate preparation for DNA replication in the following S phase. APCCdh1 target proteins are frequently upregulated in tumor cells and the inactivation of human Cdh1 might interfere with genome integrity by target stabilization. Here we show that APCCdh1 is required for maintaining genomic integrity in primary human cells. Lentiviral-delivered strong and stable suppression of Cdh1 by RNA interference (RNAi) causes aberrant accumulation of several APCCdh1 target proteins, such as cyclin A, B, Aurora A or Plk1, which control accurate and equal distribution of the genetic information to daughter cells. This induces a premature and prolonged S phase, mitotic-entry delay and defects in chromosome separation and cytokinesis. Cell cycle deregulation by stable knockdown of Cdh1 leads to activation of p53/p21 and genomic instability, which is further increased by codepletion of p53. Thus, stabilization of APCCdh1 targets may initiate aberrant DNA replication and chromosome separation, and trigger a p53 response by deregulating G1 in primary human cells.

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Acknowledgements

We thank F Cross, M Engelhardt, C Tsurumi and members of the laboratory for helpful discussions and critical reading of the manuscript and R Mertelsmann for continuous support. This work was supported by a grant from Deutsche Forschungsgemeinschaft (to RW).

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Authors and Affiliations

  1. Department of Hematology and Oncology, Albert-Ludwigs University Medical Center, Freiburg, Germany

    D Engelbert, D Schnerch, A Baumgarten & R Wäsch

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  1. D Engelbert
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  2. D Schnerch
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  3. A Baumgarten
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  4. R Wäsch
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Correspondence to R Wäsch.

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

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Engelbert, D., Schnerch, D., Baumgarten, A. et al. The ubiquitin ligase APCCdh1 is required to maintain genome integrity in primary human cells. Oncogene 27, 907–917 (2008). https://doi.org/10.1038/sj.onc.1210703

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