The XPC protein is indispensable to global genomic repair (GGR), the subpathway of nucleotide excision repair (NER), and plays an important role in the damage recognition. While XPC expression can be induced following UV irradiation it has also been found to be intrinsically unstable and is degraded by the 26S proteasome. However, hHR23B protein partly stabilizes XPC in vivo. Our previous studies have shown that XPC can be degraded independent of ubiquitylation following UV irradiation. The subunits of DDB-Cul4A E3 ligase complex differentially regulate this UV-induced XPC degradation. Besides, UV-induced sumoylation of XPC inhibits its degradation. We have now investigated the function of XPC degradation in the process of NER. We evaluated the putative sumoylation sites in XPC protein and found that K655 is the key site responsible for both XPC sumoylation and degradation. Upon mutating K655 to alanine, UV-induced XPC modification disappeared with concomitant blocking of UV-induced XPC degradation. To understand the importance of this modification site, K655A mutant form was expressed in repair-deficient XP-C cells. Our results show that K655A mutation neither affects the binding of XPC to hHR23B, nor the recruitment of XPC itself or XPB or XPA to the UV-damaged sites. However, the recruitment of XPG was compromised in the XP-C cells transfected with K655A mutant compared to those transfected with wild-type XPC. Consequently, K655A mutant was unable to restore the CPD repair capacity in XP-C cells. These results indicate that UV-induced degradation of XPC, allowing the recruitment of XPG to the damage sites, is necessary for efficient NER.

(Supported by NIH grants ES2388, ES12991 and CA93413).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA