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Vol. 12, Issue 5, 1315-1328, May 2001
Institut de Biologie Structurale Jean-Pierre Ebel (Commissariat
à l'Energie Atomique-Centre National de la Recherche
Scientifique), 38027 Grenoble Cedex 1, France
A "spindle assembly" checkpoint has been described that arrests
cells in G1 following inappropriate exit from mitosis in the presence
of microtubule inhibitors. We have here addressed the question of
whether the resulting tetraploid state itself, rather than failure of
spindle function or induction of spindle damage, acts as a checkpoint
to arrest cells in G1. Dihydrocytochalasin B induces cleavage
failure in cells where spindle function and chromatid segregation are
both normal. Notably, we show here that nontransformed REF-52 cells
arrest indefinitely in tetraploid G1 following cleavage failure. The
spindle assembly checkpoint and the tetraploidization checkpoint that
we describe here are likely to be equivalent. Both involve arrest in G1
with inactive cdk2 kinase, hypophosphorylated retinoblastoma protein,
and elevated levels of p21WAF1 and cyclin E. Furthermore,
both require p53. We show that failure to arrest in G1 following
tetraploidization rapidly results in aneuploidy. Similar tetraploid G1
arrest results have been obtained with mouse NIH3T3 and human IMR-90
cells. Thus, we propose that a general checkpoint control acts in G1 to
recognize tetraploid cells and induce their arrest and thereby prevents
the propagation of errors of late mitosis and the generation of
aneuploidy. As such, the tetraploidy checkpoint may be a critical
activity of p53 in its role of ensuring genomic integrity.
Corresponding author. E-mail address:
margolis{at}ibs.fr.
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