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p53 suppresses structural chromosome instability after mitotic arrest in human cells

Oncogene volume 29, pages 1929–1940 (2010)Cite this article

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Abstract

The p53 tumor suppressor inhibits the proliferation of cells that undergo prolonged activation of the mitotic checkpoint. However, the function of this antiproliferative response is not well defined. Here, we report that p53 suppresses structural chromosome instability after mitotic arrest in human cells. In both HCT116 colon cancer cells and normal human fibroblasts, DNA breaks occurred during mitotic arrest in a p53-independent manner, but p53 was required to suppress the proliferation and structural chromosome instability of the resulting polyploid cells. In contrast, cells made polyploid without mitotic arrest exhibited neither significant structural chromosome instability nor p53-dependent cell cycle arrest. We also observed that p53 suppressed both the frequency and structural chromosome instability of spontaneous polyploids in HCT116 cells. Furthermore, time-lapse videomicroscopy revealed that polyploidization of p53−/− HCT116 cells is frequently accompanied by mitotic arrest. These data suggest that a function of the p53-dependent postmitotic response is the prevention of structural chromosome instability after prolonged activation of the mitotic checkpoint. Accordingly, our study suggests a novel mechanism of tumor suppression for p53, as well as a potential function for p53 in the outcome of antimitotic chemotherapy.

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Acknowledgements

We thank D Pallas, P Doetsch, D Jones, A Corbett, G Davis, and M Wiltenburg for discussion and support, and B Vogelstein for providing cell lines. This work was supported in part by grants from the National Institutes of Health to VWY (DK52230, DK64399, and CA84197) and to WBD (5T32GM008367-18). This work was supported in part by grants from the National Institutes of Health to VWY (DK52230, DK64399, and CA84197) and to WBD (5T32GM008367).

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  1. Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

    W B Dalton, B Yu & V W Yang

  2. Biochemistry, Cell and Developmental Biology Graduate Program, Emory University School of Medicine, Atlanta, GA, USA

    W B Dalton, B Yu & V W Yang

  3. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    V W Yang

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Correspondence to V W Yang.

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Dalton, W., Yu, B. & Yang, V. p53 suppresses structural chromosome instability after mitotic arrest in human cells. Oncogene 29, 1929–1940 (2010). https://doi.org/10.1038/onc.2009.477

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