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Abstract

Ultraviolet (UV) radiation from sunlight is a major etiologic factor for skin cancer, the most prevalent cancer in the U.S., as well as premature skin aging. In particular, UVB radiation causes formation of specific DNA damage photoproducts between pyrimidine bases. These DNA damage photoproducts are repaired by a process called nucleotide excision repair, also known as UV-induced DNA repair. When left unrepaired, UVB-induced DNA damage leads to accumulation of mutations, predisposing people to carcinogenesis as well as to premature aging. 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. ,We also found that phosphorylation of XPC acts as a novel post-translational regulatory mechanism of the NER pathway. We show that XPC is phosphorylated at serine 94. Moreover, after UVB irradiation, XPC phosphorylation regulates recruitment of ubiquitinated XPC and its downstream NER factors to the chromatin. In addition, upon evaluating the predicted kinases for XPC phosphorylation, we found that casein kinase II (CK2) promotes NER. Furthermore, CK2 kinase mediates XPC phosphorylation at serine 94, and also promotes recruitment of ubiquitinated XPC to the chromatin after UVB irradiation. Our findings have identified XPC phosphorylation as a new mechanism for regulating NER following UV-induced DNA damage. ,Our findings have uncovered USP11 and XPC phosphorylation at S94 as novel post-translational regulators of XPC activity in NER, and have significantly increased our understanding of the molecular regulatory mechanisms of UV-induced DNA damage repair.

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