Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis

Xiaolu Ma, Hongmei Liu, Jing Li, Yihao Wang, Yue-He Ding, Hongyan Shen, Yeran Yang, Chenyi Sun, Min Huang, Yingfeng Tu, Yang Liu, Yongliang Zhao, Meng-Qiu Dong, Ping Xu, Tie-Shan Tang () and Caixia Guo ()
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Xiaolu Ma: Chinese Academy of Sciences
Hongmei Liu: Chinese Academy of Sciences
Jing Li: Capital Normal University
Yihao Wang: Beijing Institute of Radiation Medicine
Yue-He Ding: National Institute of Biological Sciences (Beijing)
Hongyan Shen: Chinese Academy of Sciences
Yeran Yang: Chinese Academy of Sciences
Chenyi Sun: Chinese Academy of Sciences
Min Huang: Chinese Academy of Sciences
Yingfeng Tu: Chinese Academy of Sciences
Yang Liu: Chinese Academy of Sciences
Yongliang Zhao: Chinese Academy of Sciences
Meng-Qiu Dong: National Institute of Biological Sciences (Beijing)
Ping Xu: Beijing Institute of Radiation Medicine
Tie-Shan Tang: Chinese Academy of Sciences
Caixia Guo: Chinese Academy of Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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 CRL4CDT2-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.

Date: 2017
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DOI: 10.1038/s41467-017-02164-1

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