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Molecular and Cellular Biology, October 2001, p. 6738-6747, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6738-6747.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Xeroderma Pigmentosum Group E Gene Product DDB2 Is a Specific Target of Cullin 4A in Mammalian Cells

Alo Nag, Tanya Bondar, Shalu Shiv, and Pradip Raychaudhuri*

Department of Biochemistry and Molecular Biology (M/C 536), University of Illinois at Chicago, Chicago, Illinois 60612

Received 22 February 2001/Returned for modification 10 May 2001/Accepted 19 July 2001

The damaged-DNA binding protein DDB consists of two subunits, DDB1 (127 kDa) and DDB2 (48 kDa). Mutations in the DDB2 subunit have been detected in patients suffering from the repair deficiency disease xeroderma pigmentosum (group E). In addition, recent studies suggested a role for DDB2 in global genomic repair. DDB2 also exhibits transcriptional activity. We showed that expression of DDB1 and DDB2 stimulated the activity of the cell cycle regulatory transcription factor E2F1. Here we show that DDB2 is a cell cycle-regulated protein. It is present at a low level in growth-arrested primary fibroblasts, and after release the level peaks at the G1/S boundary. The cell cycle regulation of DDB2 involves posttranscriptional mechanisms. Moreover, we find that an inhibitor of 26S proteasome increases the level of DDB2, suggesting that it is regulated by the ubiquitin-proteasome pathway. Our previous study indicated that the cullin family protein Cul-4A associates with the DDB2 subunit. Because cullins are involved in the ubiquitin-proteasome pathway, we investigated the role of Cul-4A in regulating DDB2. Here we show that DDB2 is a specific target of Cul-4A. Coexpression of Cul-4A, but not Cul-1 or other highly related cullins, increases the ubiquitination and the decay rate of DDB2. A naturally occurring mutant of DDB2 (2RO), which does not bind Cul-4A, is not affected by coexpression of Cul-4A. Studies presented here identify a specific function of the Cul-4A gene, which is amplified and overexpressed in breast cancers.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology (M/C 536), University of Illinois at Chicago, 1819 W. Polk St., Chicago, IL 60612. Phone: (312) 413-0255. Fax: (312) 413-0364. E-mail: Pradip{at}uic.edu.

Molecular and Cellular Biology, October 2001, p. 6738-6747, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6738-6747.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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