Nature Communications · 2017 · 52 citations · 57 references
Life SciencesMolecular BiologyOncologyCarcinogenesisDna ReplicationMolecular OncologyDna DamageDna Damage SignalingDna Double-strand Break RepairDna Polymerase FunctionDna Strand BreaksTranslesion Dna SynthesisCyclobutane Pyrimidine DimersMolecular CarcinogenesisSkin CarcinogenesisTranslesion Synthesis RegulationUltraviolet MutagenesisUltraviolet-induced Dna DamageUltraviolet-induced Lesion BypassUv-induced Dna Lesions
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 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.
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Systematic and Quantitative Assessment of the Ubiquitin-Modified Proteome
Woong Kim, Eric J. Bennett, Edward L. Huttlin et al. · Molecular Cell · 2011 · 1.6K citations · Full text
The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase η
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