Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage

Luca Busino, Maddalena Donzelli (), Massimo Chiesa, Daniele Guardavaccaro, Dvora Ganoth, N. Valerio Dorrello, Avram Hershko, Michele Pagano and Giulio F. Draetta
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Luca Busino: European Institute of Oncology
Maddalena Donzelli: European Institute of Oncology
Massimo Chiesa: European Institute of Oncology
Daniele Guardavaccaro: New York University School of Medicine and NYU Cancer Institute
Dvora Ganoth: Technion-Israel Institute of Technology
N. Valerio Dorrello: New York University School of Medicine and NYU Cancer Institute
Avram Hershko: Technion-Israel Institute of Technology
Michele Pagano: New York University School of Medicine and NYU Cancer Institute
Giulio F. Draetta: European Institute of Oncology

Nature, 2003, vol. 426, issue 6962, 87-91

Abstract: Abstract The Cdc25A phosphatase is essential for cell-cycle progression because of its function in dephosphorylating cyclin-dependent kinases. In response to DNA damage or stalled replication, the ATM and ATR protein kinases activate the checkpoint kinases Chk1 and Chk2, which leads to hyperphosphorylation of Cdc25A1,2,3. These events stimulate the ubiquitin-mediated proteolysis of Cdc25A1,4,5 and contribute to delaying cell-cycle progression, thereby preventing genomic instability1,2,3,4,5,6,7. Here we report that β-TrCP is the F-box protein that targets phosphorylated Cdc25A for degradation by the Skp1/Cul1/F-box protein complex. Downregulation of β-TrCP1 and β-TrCP2 expression by short interfering RNAs causes an accumulation of Cdc25A in cells progressing through S phase and prevents the degradation of Cdc25A induced by ionizing radiation, indicating that β-TrCP may function in the intra-S-phase checkpoint. Consistent with this hypothesis, suppression of β-TrCP expression results in radioresistant DNA synthesis in response to DNA damage—a phenotype indicative of a defect in the intra-S-phase checkpoint that is associated with an inability to regulate Cdc25A properly. Our results show that β-TrCP has a crucial role in mediating the response to DNA damage through Cdc25A degradation.

Date: 2003
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DOI: 10.1038/nature02082

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