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

Palak Shah,Seungwon Yang,Keyoumars Soltani,Lei Qiang,Yu-Ying He

doi:10.18632/oncotarget.22105

Abstract

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.

Highlights

Nucleotide excision repair (NER) is the most versatile DNA repair system for removing various forms of bulky DNA damage induced by environmental carcinogens, including solar ultraviolet B (UVB) radiation and air pollutants [1,2,3]
We focused on the repair of cyclobutane pyrimidine dimers (CPD), since CPD is the main photoproduct of UV-induced DNA damage in humans, and unrepaired CPD damage leads to skin cancer [40]
Our results indicate that ubiquitin-specific peptidase 11 (USP11) positively regulates repair of UV-induced CPD DNA damage, and suggests a tumor suppressive function of USP11 in skin cancer

Summary

Introduction

Nucleotide excision repair (NER) is the most versatile DNA repair system for removing various forms of bulky DNA damage induced by environmental carcinogens, including solar ultraviolet B (UVB) radiation and air pollutants [1,2,3]. Defective GG-NER in humans leads to the Xeroderma pigmentosum (XP) syndrome, characterized by an increased risk of carcinogenesis in various organs including the skin, lungs and brain [47]. Of the xeroderma pigmentosum complementation group A-G (XPA-XPG) factors identified in the GGNER process, XPC plays a vital role in the initial DNA damage recognition step in GG-NER [4,5,6, 11,12,13], and in preventing carcinogenesis in various organs, especially skin carcinogenesis [14,15,16,17,18]. Ubiquitination of XPC by the UV-DDB complex enhances XPC binding to the DNA damage site and is essential for its DNA damage recognition function in NER [20, 21, 24]. Even though the biochemical function of XPC in the NER process has been extensively studied, regulation of XPC by deubiquitination is largely unknown

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