Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21 (original) (raw)

Nature volume 381, pages 713–716 (1996) Cite this article

Abstract

PRECISE coordination of the S and M phases of the eukaryotic cell cycle is critical not only for normal cell division, but also for effective growth arrest under conditions of stress. When damaged, a cell must communicate signals to both the mitotic and DNA synthesis machineries so that a mitotic block is not followed by an extra S phase, or vice versa. The biochemical mechanisms regulating this coordination, termed checkpoints, have been identified in lower eukaryotes, but are largely unknown in mammalian cells1–3. Here we show that p21WAF1/CIP1, the prototype inhibitor of cyclin-dependent kinases (CDKs)4, is required for this coordination in human cells. In the absence of p21, DNA-damaged cells arrest in a G2-like state, but then undergo additional S phases without intervening normal mitoses. They thereby acquire grossly deformed, polyploid nuclei and subsequently die through apoptosis. Perhaps not by coincidence, the DNA-damaging agents that can cause S/M uncoupling are used in the clinic to kill cancer cells preferentially.

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Authors and Affiliations

  1. The Howard Hughes Medical Institute, Johns Hopkins Oncology Center, and Program in Human Genetics, 424 N. Bond Street, Baltimore, Maryland, 21231, USA
    Todd Waldman, Christoph Lengauer, Kenneth W. Kinzler & Bert Vogelstein

Authors

  1. Todd Waldman
  2. Christoph Lengauer
  3. Kenneth W. Kinzler
  4. Bert Vogelstein

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Waldman, T., Lengauer, C., Kinzler, K. et al. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21.Nature 381, 713–716 (1996). https://doi.org/10.1038/381713a0

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