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Tumor Biology |
Prevents G2 Progression to Mitotic Catastrophe in Human Colon Carcinoma Cells after DNA Damage, But p21WAF1 Induces Stable G1 Arrest in Resulting Tetraploid Cells1
Institut de Biologie Structurale Jean-Pierre Ebel (CEA-CNRS), 38027 Grenoble Cedex 1, France
p21WAF1 and 14-3-3
, which are both transcriptional products of p53, have been reported to play a role in the G2 DNA damage checkpoint in mammalian cells. Human colon carcinoma cells, isogenic except for the presence or absence of either p21WAF1 or 14-3-3 (T. A. Chan et al., Genes Dev., 14: 1584–1588, 2000), are useful models for analysis of the role of these proteins in checkpoint control. Here, we have examined mitotic behavior within a single cell cycle after DNA damage in these cell lines. Our results show that p21WAF1, but not 14-3-3, imposes a significant G2 delay after DNA damage. After G2 delay, we found that all isogenic cells, including those competent for both p21WAF1 and 14-3-3, adapt to the DNA damage checkpoint and progress into mitosis, where they undergo incomplete chromosome segregation and reenter G1 with a tetraploid DNA content. Strikingly, our results show that p21WAF1, but not 14-3-3, activates a checkpoint in response to DNA damage that prevents continued cycling of the tetraploid cells that result from a mitotic catastrophe characterized by failure to complete cell division. These results demonstrate that a tetraploid DNA content is not a reliable criterion to establish that arrest occurs in G2. Also, the DNA damage checkpoint mediated by p53-dependent induction of p21WAF1 assures neither G2 arrest nor DNA repair sufficient to enable accurate chromosome segregation in human colon carcinoma cells. We conclude that p21WAF1, but not 14-3-3, has a unique role in the induction of G1 arrest in tetraploid cells that results from mitotic catastrophe after DNA damage.
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