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RESEARCH PAPER
-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase
1 Department of Pathology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA , 2 Center for Genetics and Genomics, Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA , 3 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
Eukaryotic cells respond to DNA damage and stalled replication forks by activating protein kinase-mediated signaling pathways that promote cell cycle arrest and DNA repair. A central target of the cell cycle arrest program is the Cdc25A protein phosphatase. Cdc25A is required for S-phase entry and dephosphorylates tyrosine-15 phosphorylated Cdk1 (Cdc2) and Cdk2, positive regulators of cell division. Cdc25A is unstable during S-phase and is degraded through the ubiquitin-proteasome pathway, but its turnover is enhanced in response to DNA damage. Although basal and DNA-damage-induced turnover depends on the ATM-Chk2 and ATR-Chk1 pathways, how these kinases engage the ubiquitin ligase machinery is unknown. Here, we demonstrate a requirement for SCF
-TRCP in Cdc25A turnover during an unperturbed cell cycle and in response to DNA damage. Depletion of -TRCP stabilizes Cdc25A, leading to hyperactive Cdk2 activity. SCF-TRCP promotes Chk1-dependent Cdc25A ubiquitination in vitro, and this involves serine 76, a known Chk1 phosphorylation site. However, recognition of Cdc25A by -TRCP occurs via a noncanonical phosphodegron in Cdc25A containing phosphoserine 79 and phosphoserine 82, sites that are not targeted by Chk1. These data indicate that Cdc25A turnover is more complex than previously appreciated and suggest roles for an additional kinase(s) in Chk1-dependent Cdc25A turnover.
[Keywords: Cdc25A; Chk1; DNA damage; protein turnover; SCF ubiquitin ligase]
Received October 2, 2003; revised version accepted November 10, 2003.
4 Corresponding author.
E-MAIL wade_harper{at}hms.harvard.edu; FAX (617) 432-6591.
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