Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21

Todd Waldman, Christoph Lengauer, Kenneth W. Kinzler, Bert Vogelstein

Research output: Contribution to journalArticle

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 cells. Here we show that p21(WAF1/CIP1), the proto-type 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.

Original languageEnglish (US)
Pages (from-to)713-716
Number of pages4
JournalNature
Volume381
Issue number6584
DOIs
StatePublished - Jun 28 1996

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