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MBC in Press, published online ahead of print June 4, 2004
Mol. Biol. Cell 10.1091/mbc.E03-12-0871

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Submitted on December 4, 2003
Revised on May 26, 2004
Accepted on May 27, 2004

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

Fabienne Baus Charrier-Savournin*{dagger}, Marie-Thérèse Chateau*{ddagger}, Véronique Gire*, John Sedivy{sect}, Jacques Piette||, and Vjekoslav Dulic*¶

*CRBM-CNRS FRE 2593, 34293 Montpellier, France; {ddagger}Faculté de Pharmacie, Université de Montpellier I, 34060 Montpellier, France; {sect}Department of Molecular Biology, Cell Biology, and Biochemistry, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912; ||Centre de Recherche en Cancérologie- INSERM EMI0229, Montpellier, France

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 (NHF) 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 NHF 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.

{dagger}Present address: CEA/VALRHO-Marcoule, Service de Biochimie post-génomique et Toxicologie Nucléaire, BP 17171, 30207 Bagnols sur Cèze, France Corresponding author. E-mail: dulic{at}crbm.cnrs-mop.fr




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