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J. Biol. Chem., Vol. 281, Issue 19, 13404-13411, May 12, 2006

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Cullin 4A-mediated Proteolysis of DDB2 Protein at DNA Damage Sites Regulates in Vivo Lesion Recognition by XPC^*

Mohamed A. El-Mahdy¹, Qianzheng Zhu¹, Qi-en Wang, Gulzar Wani, Mette Prætorius-Ibba, and Altaf A. Wani^¶2

From the Departments of Radiology and Molecular and Cellular Biochemistry, and ^¶James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio 43210

Xeroderma pigmentosum (XP) complementation group E gene product, damaged DNA-binding protein 2 (DDB2), is a subunit of the DDB heterodimeric protein complex with high specificity for binding to a variety of DNA helix-distorting lesions. DDB is believed to play a role in the initial step of damage recognition in mammalian nucleotide excision repair (NER) of ultraviolet light (UV)-induced photolesions. It has been shown that DDB2 is rapidly degraded after cellular UV irradiation. However, the relevance of DDB2 degradation to its functionality in NER is still unknown. Here, we have provided evidence that Cullin 4A (CUL-4A), a key component of CUL-4A-based ubiquitin ligase, mediates DDB2 degradation at the damage sites and regulates the recruitment of XPC and the repair of cyclobutane pyrimidine dimers. We have shown that CUL-4A can be identified in a UV-responsive protein complex containing both DDB subunits. CUL-4A was visualized in localized UV-irradiated sites together with DDB2 and XPC. Degradation of DDB2 could be blocked by silencing CUL-4A using small interference RNA or by treating cells with proteasome inhibitor MG132. This blockage resulted in prolonged retention of DDB2 at the subnuclear DNA damage foci within micropore irradiated cells. Knock down of CUL-4A also decreased recruitment of the damage recognition factor, XPC, to the damaged foci and concomitantly reduced the removal of cyclobutane pyrimidine dimers from the entire genome. These results suggest that CUL-4A mediates the proteolytic degradation of DDB2 and that this degradation event, initiated at the lesion sites, regulates damage recognition by XPC during the early steps of NER.

Received for publication, November 2, 2005 , and in revised form, February 14, 2006.

^* This work was supported by Public Health Service Grants ES2388 and ES12991 from NIEHS and CA93413 from NCI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Radiology, The Ohio State University, 2001 Polaris Pkwy., Columbus, OH 43240-1000. Tel.: 614-293-0865; Fax: 614-293-0802; E-mail: wani.2{at}osu.edu.

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