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J. Biol. Chem., Vol. 281, Issue 10, 6246-6252, March 10, 2006
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From the
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, the ¶Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 021115, and the Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 151-742, Korea
Cdt1, a protein essential in G1 for licensing of origins for DNA replication, is inhibited in S-phase, both by binding to geminin and degradation by proteasomes. Cdt1 is also degraded after DNA damage to stop licensing of new origins until after DNA repair. Phosphorylation of Cdt1 by cyclin-dependent kinases promotes its binding to SCF-Skp2 E3 ubiquitin ligase, but the Cdk2/Skp2-mediated pathway is not essential for the degradation of Cdt1. Here we show that the N terminus of Cdt1 contains a second degradation signal that is active after DNA damage and in S-phase and is dependent on the interaction of Cdt1 with proliferating cell nuclear antigen (PCNA) through a PCNA binding motif. The degradation involves N-terminal ubiquitination and requires Cul4 and Ddb1 proteins, components of an E3 ubiquitin ligase implicated in protein degradation after DNA damage. Therefore PCNA, the matchmaker for many proteins involved in DNA and chromatin metabolism, also serves to promote the targeted degradation of associated proteins in S-phase or after DNA damage.
Received for publication, November 28, 2005 , and in revised form, January 9, 2006.
* The work was supported in part by National Institutes of Health Grant RO1-CA60499 (to A. D.). 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.
1 These authors contributed equally to this work.
2 Supported by the BK program from the Government of Korea.
3 To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, University of Virginia, Box 800733, 1300 Jefferson Park Ave., Jordan 1240, Charlottesville, VA 2290. Tel.: 434-924-1227; Fax: 434-924-5069; E-mail: ad8q{at}virginia.edu.
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