Pol? O-GlcNAcylation governs genome integrity during translesion DNA synthesis.
DNA polymerase ? (Pol?) 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 Pol? are involved in these processes remains largely unknown. Here, we reported that human Pol? 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 Pol? polyubiquitination at lysine 462, a delayed p97-dependent removal of Pol? from replication forks, and significantly enhanced UV-induced mutagenesis even though Pol? 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 Pol? O-GlcNAcylation in TLS regulation and genome stability maintenance and establish a new rationale to improve chemotherapeutic treatment.
Mesh Terms:
Antineoplastic Agents, Cell Line, Tumor, Cisplatin, DNA, DNA Damage, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, HEK293 Cells, Humans, Mutagenesis, N-Acetylglucosaminyltransferases, Polyubiquitin, Protein Processing, Post-Translational, Pyrimidine Dimers, Ubiquitination, Ultraviolet Rays
Antineoplastic Agents, Cell Line, Tumor, Cisplatin, DNA, DNA Damage, DNA Repair, DNA Replication, DNA-Directed DNA Polymerase, HEK293 Cells, Humans, Mutagenesis, N-Acetylglucosaminyltransferases, Polyubiquitin, Protein Processing, Post-Translational, Pyrimidine Dimers, Ubiquitination, Ultraviolet Rays
Nat Commun
Date: Dec. 05, 2017
PubMed ID: 29208956
View in: Pubmed Google Scholar
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