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MBC in Press, published online ahead of print December 27, 2007
Mol. Biol. Cell 10.1091/mbc.E07-09-0859

A more recent version of this article appeared on March 1, 2008
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Submitted on September 4, 2007
Revised on November 27, 2007
Accepted on December 19, 2007

Identification of Novel Human Cdt1-Binding Proteins by a Proteomics Approach: Proteolytic Regulation by APC/CCdh1

Nozomi Sugimoto,*{dagger} Issay Kitabayashi,{ddagger} Satoko Osano,*{dagger} Yasutoshi Tatsumi,* Takashi Yugawa,* Mako Narisawa-Saito,* Akio Matsukage,{dagger} Tohru Kiyono,* and Masatoshi Fujita*

*Virology Division and {ddagger}Molecular Oncology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuohku, Tokyo 104-0045, Japan; {dagger}Faculty of Science, Japan Women’s University, 2-8-1 Mejirodai, Bunkyouku, Tokyo 112-8679, Japan

Monitoring Editor: Orna Cohen-Fix

In mammalian cells, Cdt1 activity is strictly controlled by multiple independent mechanisms, implying that it is central to the regulation of DNA replication during the cell cycle. In fact, unscheduled Cdt1 hyperfunction results in rereplication and/or chromosomal damage. Thus, it is important to understand its function and regulations precisely. We sought to comprehensively identify human Cdt1-binding proteins by a combination of Cdt1 affinity chromatography and liquid chromatography and tandem mass spectrometry analysis. Through this approach, we could newly identify 11 proteins, including subunits of anaphase-promoting complex/cyclosome (APC/C), SNF2H and WSTF, topoisomerase I and II{alpha}, GRWD1/WDR28, nucleophosmin/nucleoplasmin, and importins. In vivo interactions of Cdt1 with APC/CCdh1, SNF2H, topoisomerase I and II{alpha}, and GRWD1/WDR28 were confirmed by coimmunoprecipitation assays. A further focus on APC/CCdh1 indicated that this ubiquitin ligase controls the levels of Cdt1 during the cell cycle via three destruction boxes in the Cdt1 N-terminus. Notably, elimination of these destruction boxes resulted in induction of strong rereplication and chromosomal damage. Thus, in addition to SCFSkp2 and cullin4-based ubiquitin ligases, APC/CCdh1 is a third ubiquitin ligase that plays a crucial role in proteolytic regulation of Cdt1 in mammalian cells.

Address correspondence to: Masatoshi Fujita (mafujita{at}gan2.res.ncc.go.jp)




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