Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis

DNA polymerase. (Pol eta) 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 CRL4(CDT2)-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.