p53 suppresses structural chromosome instability after mitotic arrest in human cells.
The p53 tumor suppressor inhibits the proliferation of cells that undergo prolonged activation of the mitotic checkpoint. However, the function of this antiproliferative response is not well defined. Here, we report that p53 suppresses structural chromosome instability after mitotic arrest in human cells. In both HCT116 colon cancer cells and normal human fibroblasts, DNA breaks occurred during mitotic arrest in a p53-independent manner, but p53 was required to suppress the proliferation and structural chromosome instability of the resulting polyploid cells. In contrast, cells made polyploid without mitotic arrest exhibited neither significant structural chromosome instability nor p53-dependent cell cycle arrest. We also observed that p53 suppressed both the frequency and structural chromosome instability of spontaneous polyploids in HCT116 cells. Furthermore, time-lapse videomicroscopy revealed that polyploidization of p53(-/-) HCT116 cells is frequently accompanied by mitotic arrest. These data suggest that a function of the p53-dependent postmitotic response is the prevention of structural chromosome instability after prolonged activation of the mitotic checkpoint. Accordingly, our study suggests a novel mechanism of tumor suppression for p53, as well as a potential function for p53 in the outcome of antimitotic chemotherapy.
Dalton
W B
WB
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Yu
B
B
Yang
V W
VW
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival; D043171:Chromosomal Instability / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D045325:HCT116 Cells / Q000473:pathology; D006801:Humans; D008938:Mitosis / Q000502:physiology; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology; D011123:Polyploidy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53