抄録
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.
| 元の言語 | 英語 |
|---|---|
| ページ（範囲） | 1126-1136 |
| ページ数 | 11 |
| ジャーナル | EMBO Journal |
| 巻 | 25 |
| 発行部数 | 5 |
| DOI | |
| 出版物ステータス | 出版済み - 3 8 2006 |
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All Science Journal Classification (ASJC) codes
- Neuroscience(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
これを引用
Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. / 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.
：: EMBO Journal, 巻 25, 番号 5, 08.03.2006, p. 1126-1136.研究成果: ジャーナルへの寄稿 › 記事
}
TY - JOUR
T1 - Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis
AU - Nishitani, Hideo
AU - Sugimoto, Nozomi
AU - Roukos, Vassilis
AU - Nakanishi, Yohsuke
AU - Saijo, Masafumi
AU - Obuse, Chikashi
AU - Tsurimoto, Toshiki
AU - Nakayama, Keiichi I.
AU - Nakayama, Keiko
AU - Fujita, Masatoshi
AU - Lygerou, Zoi
AU - Nishimoto, Takeharu
PY - 2006/3/8
Y1 - 2006/3/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33644861713&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644861713&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7601002
DO - 10.1038/sj.emboj.7601002
M3 - Article
C2 - 16482215
AN - SCOPUS:33644861713
VL - 25
SP - 1126
EP - 1136
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 5
ER -