Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis

• Published in: Nature communications Vol. 8; no. 1; pp. 1941 - 14
• Main Authors: Ma, Xiaolu, Liu, Hongmei, Li, Jing, Wang, Yihao, Ding, Yue-He, Shen, Hongyan, Yang, Yeran, Sun, Chenyi, Huang, Min, Tu, Yingfeng, Liu, Yang, Zhao, Yongliang, Dong, Meng-Qiu, Xu, Ping, Tang, Tie-Shan, Guo, Caixia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.12.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/1427/2354; 631/337/458/1524; 631/337/458/582; Carcinogenesis; Carcinogens; Chemical synthesis; Cisplatin; Cyclobutane; Cyclobutane pyrimidine dimers; Deoxyribonucleic acid; Dimers; DNA; DNA biosynthesis; DNA damage; DNA polymerase; DNA-directed DNA polymerase; Gene expression; Genomes; Humanities and Social Sciences; Irradiation; Lesions; Lysine; multidisciplinary; Mutagenesis; O-GlcNAcylation; Post-translation; Replication forks; Science; Science (multidisciplinary); Skin diseases; Threonine; Ultraviolet radiation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02164-1

DNA polymerase η (Polη) facilitates translesion DNA synthesis (TLS) across ultraviolet (UV) irradiation- and cisplatin-induced DNA lesions implicated in skin carcinogenesis and chemoresistant phenotype formation, respectively. However, whether post-translational modifications of Polη are involved in these processes remains largely unknown. Here, we reported that human Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase upon DNA damage. Abrogation of this modification results in a reduced level of CRL4 CDT2 -dependent Polη polyubiquitination at lysine 462, a delayed p97-dependent removal of Polη from replication forks, and significantly enhanced UV-induced mutagenesis even though Polη focus formation and its efficacy to bypass across cyclobutane pyrimidine dimers after UV irradiation are not affected. Furthermore, the O-GlcNAc-deficient T457A mutation impairs TLS to bypass across cisplatin-induced lesions, causing increased cellular sensitivity to cisplatin. Our findings demonstrate a novel role of Polη O-GlcNAcylation in TLS regulation and genome stability maintenance and establish a new rationale to improve chemotherapeutic treatment. Polη is a key player in translesion DNA synthesis. Here, the authors uncover that, in response to DNA damage, Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase to facilitate the timely disassembly of Polη after DNA lesion bypass.