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J. Biol. Chem., Vol. 280, Issue 42, 35299-35309, October 21, 2005

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Proliferating Cell Nuclear Antigen Recruits Cyclin-dependent Kinase Inhibitor Xic1 to DNA and Couples Its Proteolysis to DNA Polymerase Switching^*

From the University of Texas Health Science Center at San Antonio, Department of Molecular Medicine, Institute of Biotechnology, San Antonio, Texas 78245-3207

The Xenopus cyclin-dependent kinase (CDK) inhibitor, p27^Xic1 (Xic1), binds to CDK2-cyclins and proliferating cell nuclear antigen (PCNA), inhibits DNA synthesis in Xenopus extracts, and is targeted for ubiquitin-mediated proteolysis. Previous studies suggest that Xic1 ubiquitination and degradation are coupled to the initiation of DNA replication, but the precise timing and molecular mechanism of Xic1 proteolysis has not been determined. Here we demonstrate that Xic1 proteolysis is temporally restricted to late replication initiation following the requirements for DNA polymerase -primase, replication factor C, and PCNA. Our studies also indicate that Xic1 degradation is absolutely dependent upon the binding of Xic1 to PCNA in both Xenopus egg and gastrulation stage extracts. Additionally, extracts depleted of PCNA do not support Xic1 proteolysis. Importantly, while the addition of recombinant wild-type PCNA alone restores Xic1 degradation, the addition of a PCNA mutant defective for trimer formation does not restore Xic1 proteolysis in PCNA-depleted extracts, suggesting Xic1 proteolysis requires both PCNA binding to Xic1 and the ability of PCNA to be loaded onto primed DNA by replication factor C. Taken together, our studies suggest that Xic1 is targeted for ubiquitination and degradation during DNA polymerase switching through its interaction with PCNA at a site of initiation.

Received for publication, June 13, 2005 , and in revised form, August 3, 2005.

^* This work was supported by Career Development Award DAMD17-02-1-0589) from the United States Army Department of Defense and by National Institutes of Health Grant 1RO1-GM066226. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ Current address: Dept. of Molecular Biology, The Scripps Research Inst., 10550 N. Torrey Pines Rd., MB-7, La Jolla, CA 92037.

² To whom correspondence should be addressed. Tel.: 210-567-7263; Fax: 210-567-7247; E-mail: yew{at}uthscsa.edu.

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