Translesion synthesis
TLS polymerase eta (Polη) is specifically required for error-free bypass of UV-induced cyclobutane pyrimidine dimers (CPDs). Translesion DNA synthesis (TLS) is one mode of DNA damage tolerance, which utilizes specialized TLS polymerases to sustain DNA synthesis when encountering obstacles. However, more precise mechanism for Parkin’s function in preventing carcinogenesis still needs to be elucidated. Several biological functions of Parkin have been implicated in tumor suppression, such as the role as a pivotal mediator of mitophagy and the role as a regulator of cell cycle progression. Parkin knockout mice also exhibit higher susceptibility to tumorigenesis, suggesting a role of Parkin in suppressing tumorigenesis. In addition to being associated with the progression of parkinsonism, Parkin deficiency is also frequently detected in a broad spectrum of tumors and tumor-derived cell lines, including melanoma, glioma, ovarian cancer, cervical cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, and gastric cancer. PARK2 gene, which is frequently found mutated in early-onset Parkinson’s disease (PD), encodes an evolutionarily conserved RING-between-RING E3 ubiquitin ligase Parkin.
Translesion synthesis skin#
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. Consequently, depletion of Parkin leads to increased UV-induced mutagenesis. 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. 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. In this study, we show that depletion of Parkin causes compromised cell viability and genome stability after ultraviolet (UV) radiation. Notably, PD patients also exhibit a significantly higher risk in melanoma and other skin tumors, while the mechanism remains largely unknown. Received: JanuAccepted: MaPublished: April 05, 2017ĭeficiency of Parkin is a major cause of early-onset Parkinson’s disease (PD). *These authors contributed equally to this workĬaixia Guo, email: Tang, email: Parkin, translesion DNA synthesis, ultraviolet radiation, melanoma, Parkinson’s disease 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 1ġState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, ChinaĢCAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China