HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 280/42/35299    most recent M506429200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chuang, L.-C. Articles by Yew, P. R. Search for Related Content PubMed PubMed Citation Articles by Chuang, L.-C. Articles by Yew, P. R. Related Collections Papers Of The Week Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. V. Singh, R. Warin, D. Xiao, A. A. Powolny, S. D. Stan, J. A. Arlotti, Y. Zeng, E.-R. Hahm, S. W. Marynowski, A. Bommareddy, et al. Sulforaphane Inhibits Prostate Carcinogenesis and Pulmonary Metastasis in TRAMP Mice in Association with Increased Cytotoxicity of Natural Killer Cells Cancer Res., March 1, 2009; 69(5): 2117 - 2125. [Abstract] [Full Text] [PDF]

				S. V. Singh, A. A. Powolny, S. D. Stan, D. Xiao, J. A. Arlotti, R. Warin, E.-R. Hahm, S. W. Marynowski, A. Bommareddy, D. M. Potter, et al. Garlic Constituent Diallyl Trisulfide Prevents Development of Poorly Differentiated Prostate Cancer and Pulmonary Metastasis Multiplicity in TRAMP Mice Cancer Res., November 15, 2008; 68(22): 9503 - 9511. [Abstract] [Full Text] [PDF]

				H. Nishitani, Y. Shiomi, H. Iida, M. Michishita, T. Takami, and T. Tsurimoto CDK Inhibitor p21 Is Degraded by a Proliferating Cell Nuclear Antigen-coupled Cul4-DDB1Cdt2 Pathway during S Phase and after UV Irradiation J. Biol. Chem., October 24, 2008; 283(43): 29045 - 29052. [Abstract] [Full Text] [PDF]

				T. Senga, U. Sivaprasad, W. Zhu, J. H. Park, E. E. Arias, J. C. Walter, and A. Dutta PCNA Is a Cofactor for Cdt1 Degradation by CUL4/DDB1-mediated N-terminal Ubiquitination J. Biol. Chem., March 10, 2006; 281(10): 6246 - 6252. [Abstract] [Full Text] [PDF]

				L.-C. Chuang, X.-N. Zhu, C. R. Herrera, H.-M. Tseng, C. M. Pfleger, K. Block, and P. R. Yew The C-terminal Domain of the Xenopus Cyclin-dependent Kinase Inhibitor, p27Xic1, Is Both Necessary and Sufficient for Phosphorylation-independent Proteolysis J. Biol. Chem., October 21, 2005; 280(42): 35290 - 35298. [Abstract] [Full Text] [PDF]