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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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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DOI: https://doi.org/10.1038/381713a0
