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Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication

¹ The Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; ² Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; ³ Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; ⁴ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; ⁵ Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA; ⁶ Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

Deregulation of cyclin D1 occurs in numerous human cancers through mutations, alternative splicing, and gene amplification. Although cancer-derived cyclin D1 mutants are potent oncogenes in vitro and in vivo, the mechanisms whereby they contribute to neoplasia are poorly understood. We now provide evidence derived from both mouse models and human cancer-derived cells revealing that nuclear accumulation of catalytically active mutant cyclin D1/CDK4 complexes triggers DNA rereplication, resulting from Cdt1 stabilization, which in turn triggers the DNA damage checkpoint and p53-dependent apoptosis. Loss of p53 through mutations or targeted deletion results in increased genomic instability and neoplastic growth. Collectively, the data presented reveal mechanistic insights into how uncoupling of critical cell cycle regulatory events will perturb DNA replication fidelity, thereby contributing to neoplastic transformation.

[Keywords: Cdt1; Cul4; cyclin D1T286A; cyclin D1P287A; rereplication; p53; genomic instability]]

Received June 22, 2007; revised version accepted September 21, 2007.

E-MAIL adiehl{at}mail.med.upenn.edu; FAX (215) 746-5511.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1586007

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