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Molecular and Cellular Biology, April 2006, p. 2531-2539, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2531-2539.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cul4A and DDB1 Associate with Skp2 To Target p27Kip1 for Proteolysis Involving the COP9 Signalosome{dagger}

Tanya Bondar,1,{ddagger},§ Anna Kalinina,2,§ Lyne Khair,1 Dragana Kopanja,1 Alo Nag,1,¶ Srilata Bagchi,2* and Pradip Raychaudhuri1*

Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, Illinois 60607,1 Center of Molecular Biology of Oral Diseases (M/C 860), College of Dentistry, University of Illinois at Chicago, 801 S. Paulina Ave., Chicago, Illinois 606122

Received 6 July 2005/ Returned for modification 18 October 2005/ Accepted 6 January 2006

DDB1, a subunit of the damaged-DNA binding protein DDB, has been shown to function also as an adaptor for Cul4A, a member of the cullin family of E3 ubiquitin ligase. The Cul4A-DDB1 complex remains associated with the COP9 signalosome, and that interaction is conserved from fission yeast to human. Studies with fission yeast suggested a role of the Pcu4-Ddb1-signalosome complex in the proteolysis of the replication inhibitor Spd1. Here we provide evidence that the function of replication inhibitor proteolysis is conserved in the mammalian DDB1-Cul4A-signalosome complex. We show that small interfering RNA-mediated knockdown of DDB1, CSN1 (a subunit of the signalosome), and Cul4A in mammalian cells causes an accumulation of p27Kip1. Moreover, expression of DDB1 reduces the level of p27Kip1 by increasing its decay rate. The DDB1-induced proteolysis of p27Kip1 requires signalosome and Cul4A, because DDB1 failed to increase the decay rate of p27Kip1 in cells deficient in CSN1 or Cul4A. Surprisingly, the DDB1-induced proteolysis of p27Kip1 also involves Skp2, an F-box protein that allows targeting of p27Kip1 for ubiquitination by the Skp1-Cul1-F-box complex. Moreover, we provide evidence for a physical association between Cul4A, DDB1, and Skp2. We speculate that the F-box protein Skp2, in addition to utilizing Cul1-Skp1, utilizes Cul4A-DDB1 to induce proteolysis of p27Kip1.

* Corresponding author. Mailing address for Srilata Bagchi: Center of Molecular Biology of Oral Diseases (M/C 860), College of Dentistry, University of Illinois at Chicago, 801 S. Paulina Ave., Chicago, IL 60612. Phone: (312) 413-0683. Fax: (312) 413-1604. E-mail: sbagchi{at}uic.edu. Mailing address for Pradip Raychaudhuri: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, IL 60607. Phone: (312) 413-0255. Fax: (312) 355-3847. E-mail: Pradip{at}uic.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Section of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520.

§ These two authors made equal contributions to this work.

Present address: Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201.

Molecular and Cellular Biology, April 2006, p. 2531-2539, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2531-2539.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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