Parkin regulates translesion DNA synthesis in response to UV radiation

// Xuefei Zhu 1, * , Xiaolu Ma 2, * , Yingfeng Tu 1, * , Min Huang 2 , Hongmei Liu 1 , Fengli Wang 1 , Juanjuan Gong 1 , Jiuqiang Wang 1 , Xiaoling Li 1 , Qian Chen 1 , Hongyan Shen 2 , Shu Zhu 1 , Yun Wang 1 , Yang Liu 2 , Caixia Guo 2 , Tie-Shan Tang 1 1 State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China 2 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China * These authors contributed equally to this work Correspondence to: Caixia Guo, email: guocx@big.ac.cn Tie-Shan Tang, email: tangtsh@ioz.ac.cn Keywords: Parkin, translesion DNA synthesis, ultraviolet radiation, melanoma, Parkinson’s disease Received: January 23, 2017      Accepted: March 27, 2017      Published: April 05, 2017 ABSTRACT Deficiency of Parkin is a major cause of early-onset Parkinson’s disease (PD). Notably, PD patients also exhibit a significantly higher risk in melanoma and other skin tumors, while the mechanism remains largely unknown. In this study, we show that depletion of Parkin causes compromised cell viability and genome stability after ultraviolet (UV) radiation. We demonstrate that Parkin promotes efficient Rad18-dependent proliferating cell nuclear antigen (PCNA) monoubiquitination by facilitating the formation of Replication protein A (RPA)-coated ssDNA upon UV radiation. Furthermore, Parkin is found to physically interact with NBS1 (Nijmegen breakage syndrome 1), and to be required for optimal recruitment of NBS1 and DNA polymerase eta (Polη) to UV-induced damage sites. Consequently, depletion of Parkin leads to increased UV-induced mutagenesis. These findings unveil an important role of Parkin in protecting genome stability through positively regulating translesion DNA synthesis (TLS) upon UV damage, providing a novel mechanistic link between Parkin deficiency and predisposition to skin cancers in PD patients.