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Vol. 15, Issue 9, 3965-3976, September 2004

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p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

Fabienne Baus Charrier-Savournin ^* , Marie-Thérèse Château ^* , Véronique Gire ^*, John Sedivy , Jacques Piette ^||, and Vjekoslav Duli ^* ¶

^* CRBM-Centre National de la Recherche Scientifique FRE 2593, 34293 Montpellier, France; Faculté de Pharmacie, Université de Montpellier I, 34060 Montpellier, France; Department of Molecular Biology, Cell Biology, and Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI 02912; and ^|| Centre de Recherche en Cancérologie-Institut National de la Santé et de la Recherche Médicale EMI0229, Montpellier, France

Submitted December 4, 2003; Revised May 26, 2004; Accepted May 27, 2004
Monitoring Editor: Mark Solomon

G2 arrest of cells suffering DNA damage in S phase is crucial to avoid their entry into mitosis, with the concomitant risks of oncogenic transformation. According to the current model, signals elicited by DNA damage prevent mitosis by inhibiting both activation and nuclear import of cyclin B1-Cdk1, a master mitotic regulator. We now show that normal human fibroblasts use additional mechanisms to block activation of cyclin B1-Cdk1. In these cells, exposure to nonrepairable DNA damage leads to nuclear accumulation of inactive cyclin B1-Cdk1 complexes. This nuclear retention, which strictly depends on association with endogenous p21, prevents activation of cyclin B1-Cdk1 by Cdc25 and Cdk-activating kinase as well as its recruitment to the centrosome. In p21-deficient normal human fibroblasts and immortal cell lines, cyclin B1 fails to accumulate in the nucleus and could be readily detected at the centrosome in response to DNA damage. Therefore, in normal cells, p21 exerts a dual role in mediating DNA damage-induced cell cycle arrest and exit before mitosis. In addition to blocking pRb phosphorylation, p21 directly prevents mitosis by inactivating and maintaining the inactive state of mitotic cyclin-Cdk complexes. This, with subsequent degradation of mitotic cyclins, further contributes to the establishment of a permanent G2 arrest.

Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

Present address: CEA/VALRHO-Marcoule, Service de Biochimie post-génomique et Toxicologie Nucléaire, BP 17171, 30207 Bagnols sur Cèze, France.

^¶ Corresponding author. E-mail address: dulic{at}crbm.cnrs-mop.fr.

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