Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21.
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 prototype inhibitor of cyclin-dependent kinases (CDKs), 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.
Waldman
T
T
The Howard Hughes Medical Institute, Johns Hopkins Oncology Center, and Program in Human Genetics, Baltimore, Maryland 21231, USA.
Lengauer
C
C
Kinzler
K W
KW
Vogelstein
B
B
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D006690:Bisbenzimidazole; D002166:Camptothecin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000502:physiology*; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors; D005047:Etoposide / Q000494:pharmacology; D005456:Fluorescent Dyes; D005720:Gamma Rays; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D005047:Etoposide; D004317:Doxorubicin; D018844:Cyclin-Dependent Kinases; D006690:Bisbenzimidazole; D002166:Camptothecin