PCNA recruits CDK inhibitor Xic1 to DNA and couples its proteolysis to DNA polymerase switching

doi:10.1074/jbc.M506429200

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Papers In Press, published online ahead of print August 23, 2005
J. Biol. Chem, 10.1074/jbc.M506429200
Submitted on June 13, 2005
Revised on August 3, 2005
Accepted on August 23, 2005

PCNA recruits CDK inhibitor Xic1 to DNA and couples its proteolysis to DNA polymerase switching

Li-Chiou Chuang and P. Renee Yew

Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245-3207

Corresponding Author: yew{at}uthscsa.edu

The Xenopus cyclin-dependent kinase (CDK) inhibitor, p27Xic1 (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 a/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 wildtype 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 RFC. 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.

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