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Nat Commun. 2017 Dec 5;8(1):1941. doi: 10.1038/s41467-017-02164-1.

Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis.

Author information

1
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.
2
State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.
3
Beijing Key Laboratory of DNA Damage Response, College of Life Sciences, Capital Normal University, Beijing, 100048, China.
4
State Key Laboratory of Proteomics National Center for Protein Sciences Beijing, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, Beijing Institute of Radiation Medicine, Beijing, 102206, China.
5
National Institute of Biological Sciences (Beijing), Beijing, 102206, China.
6
State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China. tangtsh@ioz.ac.cn.
7
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. guocx@big.ac.cn.

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.

PMID:
29208956
PMCID:
PMC5717138
DOI:
10.1038/s41467-017-02164-1
[Indexed for MEDLINE]
Free PMC Article

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