Regulation of XPC deubiquitination by USP11 in repair of UV-induced DNA damage

Nucleotide excision repair (NER) is the most versatile DNA repair pathway for removing DNA damage caused by UV radiation and many environmental carcinogens. NER is essential for suppressing tumorigenesis in the skin, lungs and brain. Although the core NER proteins have been identified and characterized, molecular regulation of NER remains poorly understood. Here we show that ubiquitin-specific peptidase 11 (USP11) positively regulates NER by deubiquitinating xeroderma pigmentosum complementation group C (XPC) and promoting its retention at the DNA damage sites. In addition, UV irradiation induces both USP11 recruitment to the chromatin and USP11 interaction with XPC in an XPC-ubiquitination-dependent manner. Furthermore, we found that USP11 is down-regulated in chronically UV-exposed mouse skin and in skin tumors from mice and humans. Our findings indicate that USP11 plays an important role in maintaining NER capacity, and suggest that USP11 acts as a tumor suppressor via its role in DNA repair.