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Molecular and Cellular Biology, January 2008, p. 177-187, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00880-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Xeroderma Pigmentosum Group E Gene Product DDB2 Activates Nucleotide Excision Repair by Regulating the Level of p21^{Waf1/Cip1 ,}

Tanya Stoyanova, Taewon Yoon, Dragana Kopanja, Margalit B. Mokyr, and Pradip Raychaudhuri^*

Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, Illinois 60607

Received 18 May 2007/ Returned for modification 12 June 2007/ Accepted 21 October 2007

The xeroderma pigmentosum group E gene product DDB2, a protein involved in nucleotide excision repair (NER), associates with the E3 ubiquitin ligase complex Cul4A-DDB1. But the precise role of these interactions in the NER activity of DDB2 is unclear. Several models, including DDB2-mediated ubiquitination of histones in UV-irradiated cells, have been proposed. But those models lack clear genetic evidence. Here we show that DDB2 participates in NER by regulating the cellular levels of p21^Waf1/Cip1. We show that DDB2 enhances nuclear accumulation of DDB1, which binds to a modified form of p53 containing phosphorylation at Ser18 (p53^S18P) and targets it for degradation in low-dose-UV-irradiated cells. DDB2^–/– mouse embryonic fibroblasts (MEFs), unlike wild-type MEFs, are deficient in the proteolysis of p53^S18P. Accumulation of p53^S18P in DDB2^–/– MEFs causes higher expression p21^Waf1/Cip1. We show that the increased expression of p21^Waf1/Cip1 is the cause NER deficiency in DDB2^–/– cells because deletion or knockdown of p21^Waf1/Cip1 reverses their NER-deficient phenotype. p21^Waf1/Cip1 was shown to bind PCNA, which is required for both DNA replication and NER. Moreover, an increased level of p21^Waf1/Cip1 was shown to inhibit NER both in vitro and in vivo. Our results provide genetic evidence linking the regulation of p21^Waf1/Cip1 to the NER activity of DDB2.

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* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607. Phone: (312) 413-0255. Fax: (312) 355-3847. E-mail: Pradip{at}uic.edu

Published ahead of print on 29 October 2007.

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

Present address: Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637.

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Molecular and Cellular Biology, January 2008, p. 177-187, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00880-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Stoyanova, T., Roy, N., Kopanja, D., Bagchi, S., Raychaudhuri, P. (2009). DDB2 decides cell fate following DNA damage. Proc. Natl. Acad. Sci. USA 106: 10690-10695 [Abstract] [Full Text]  
• Abbas, T., Sivaprasad, U., Terai, K., Amador, V., Pagano, M., Dutta, A. (2008). PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev. 22: 2496-2506 [Abstract] [Full Text]