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- Title
Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis.
- Authors
Nishitani, Hideo; Sugimoto, Nozomi; Roukos, Vassilis; Nakanishi, Yohsuke; Saijo, Masafumi; Obuse, Chikashi; Tsurimoto, Toshiki; Nakayama, Keiichi I; Nakayama, Keiko; Fujita, Masatoshi; Lygerou, Zoi; Nishimoto, Takeharu
- Abstract
Replication licensing is carefully regulated to restrict replication to once in a cell cycle. In higher eukaryotes, regulation of the licensing factor Cdt1 by proteolysis and Geminin is essential to prevent re-replication. We show here that the N-terminal 100 amino acids of human Cdt1 are recognized for proteolysis by two distinct E3 ubiquitin ligases during S-G2 phases. Six highly conserved amino acids within the 10 first amino acids of Cdt1 are essential for DDB1-Cul4-mediated proteolysis. This region is also involved in proteolysis following DNA damage. The second E3 is SCF-Skp2, which recognizes the Cy-motif-mediated Cyclin E/A-cyclin-dependent kinase-phosphorylated region. Consistently, in HeLa cells cosilenced of Skp2 and Cul4, Cdt1 remained stable in S-G2 phases. The Cul4-containing E3 is active during ongoing replication, while SCF-Skp2 operates both in S and G2 phases. PCNA binds to Cdt1 through the six conserved N-terminal amino acids. PCNA is essential for Cul4- but not Skp2-directed degradation during DNA replication and following ultraviolet-irradiation. Our data unravel multiple distinct pathways regulating Cdt1 to block re-replication.
- Publication
The EMBO journal, 2006, Vol 25, Issue 5, p1126
- ISSN
0261-4189
- Publication type
Journal Article
- DOI
10.1038/sj.emboj.7601002