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Molecular and Cellular Biology, July 2007, p. 4708-4719, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02432-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mammalian DET1 Regulates Cul4A Activity and Forms Stable Complexes with E2 Ubiquitin-Conjugating Enzymes{triangledown}

Elah Pick,1 On-Sun Lau,1 Tomohiko Tsuge,2,3 Suchithra Menon,1 Yingchun Tong,1 Naoshi Dohmae,3 Scott M. Plafker,4 Xing Wang Deng,1 and Ning Wei1*

Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520,1 Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan,2 Biomolecular Characterization, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan,3 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 731044

Received 29 December 2006/ Returned for modification 12 February 2007/ Accepted 17 April 2007

DET1 (de-etiolated 1) is an essential negative regulator of plant light responses, and it is a component of the Arabidopsis thaliana CDD complex containing DDB1 and COP10 ubiquitin E2 variant. Human DET1 has recently been isolated as one of the DDB1- and Cul4A-associated factors, along with an array of WD40-containing substrate receptors of the Cul4A-DDB1 ubiquitin ligase. However, DET1 differs from conventional substrate receptors of cullin E3 ligases in both biochemical behavior and activity. Here we report that mammalian DET1 forms stable DDD-E2 complexes, consisting of DDB1, DDA1 (DET1, DDB1 associated 1), and a member of the UBE2E group of canonical ubiquitin-conjugating enzymes. DDD-E2 complexes interact with multiple ubiquitin E3 ligases. We show that the E2 component cannot maintain the ubiquitin thioester linkage once bound to the DDD core, rendering mammalian DDD-E2 equivalent to the Arabidopsis CDD complex. While free UBE2E-3 is active and able to enhance UbcH5/Cul4A activity, the DDD core specifically inhibits Cul4A-dependent polyubiquitin chain assembly in vitro. Overexpression of DET1 inhibits UV-induced CDT1 degradation in cultured cells. These findings demonstrate that the conserved DET1 complex modulates Cul4A functions by a novel mechanism.

* Corresponding author. Mailing address: OML 451, Department of MCDB, Yale University, New Haven, CT 06520. Phone: (203) 432-3897. Fax: (203) 432-3854. E-mail: ning.wei{at}yale.edu

{triangledown} Published ahead of print on 23 April 2007.

Molecular and Cellular Biology, July 2007, p. 4708-4719, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02432-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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