Chromosoma

, Volume 120, Issue 1, pp 73–82 | Cite as

Replication-compromised cells require the mitotic checkpoint to prevent tetraploidization

  • Zilai Zhang
  • Sumit Arora
  • Yanjiao Zhou
  • Athena Cherry
  • Teresa S.-F. Wang
Research Article

Abstract

Replication stress often induces chromosome instability. In this study, we explore which factors in replication-compromised cells promote abnormal chromosome ploidy. We expressed mutant forms of either polymerase α (Polα) or polymerase δ (Polδ) in normal human fibroblasts to compromise DNA replication. Cells expressing the mutant Polα-protein failed to sustain mitotic arrest and, when propagated progressively, down-regulated Mad2 and BubR1 and accumulated 4N-DNA from the 2N-DNA cells. Significantly, a population of these cells became tetraploids. The Polα mutant expressing cells also exhibited elevated cellular senescence markers, suggesting as a mechanism to limit proliferation of the tetraploids. Expression of the Polδ mutant also caused cells to accumulate 4N-DNA. In contrast to the Polα mutant expressing cells, the Polδ mutant expressing cells expressed sufficient levels of Mad2, BubR1, and cyclin B1 to sustain mitotic arrest, and these cells had normal chromosome ploidy. Together, these results suggest that replication-compromised cells depend on the mitotic checkpoint to prevent mitotic slippage that could result in tetraploidization.

Notes

Acknowledgments

We thank Dr. Guowei Fang of Stanford University for antibodies against Mad2 and BubR1. This work is supported by grants from National Cancer Institute of National Institutes of Health. Z. Z. is partially supported by the Dean’s Fellowship of Stanford University School of Medicine.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Zilai Zhang
    • 1
  • Sumit Arora
    • 1
  • Yanjiao Zhou
    • 1
  • Athena Cherry
    • 1
  • Teresa S.-F. Wang
    • 1
  1. 1.Department of PathologyStanford University Medical CenterStanfordUSA

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