RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair
In: Cell Death and Disease, Jg. 15 (2024), Heft 5, S. 1-11
Online
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Zugriff:
Abstract RAD18, an important ubiquitin E3 ligase, plays a dual role in translesion DNA synthesis (TLS) and homologous recombination (HR) repair. However, whether and how the regulatory mechanism of O-linked N-acetylglucosamine (O-GlcNAc) modification governing RAD18 and its function during these processes remains unknown. Here, we report that human RAD18, can undergo O-GlcNAcylation at Ser130/Ser164/Thr468, which is important for optimal RAD18 accumulation at DNA damage sites. Mechanistically, abrogation of RAD18 O-GlcNAcylation limits CDC7-dependent RAD18 Ser434 phosphorylation, which in turn significantly reduces damage-induced PCNA monoubiquitination, impairs Polη focus formation and enhances UV sensitivity. Moreover, the ubiquitin and RAD51C binding ability of RAD18 at DNA double-strand breaks (DSBs) is O-GlcNAcylation-dependent. O-GlcNAcylated RAD18 promotes the binding of RAD51 to damaged DNA during HR and decreases CPT hypersensitivity. Our findings demonstrate a novel role of RAD18 O-GlcNAcylation in TLS and HR regulation, establishing a new rationale to improve chemotherapeutic treatment.
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RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair
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Autor/in / Beteiligte Person: | Ma, Xiaolu ; Fu, Hui ; Sun, Chenyi ; Wu, Wei ; Hou, Wenya ; Zhou, Zibin ; Zheng, Hui ; Gong, Yifei ; Wu, Honglin ; Qin, Junying ; Lou, Huiqiang ; Li, Jing ; Tang, Tie-Shan ; Guo, Caixia |
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Zeitschrift: | Cell Death and Disease, Jg. 15 (2024), Heft 5, S. 1-11 |
Veröffentlichung: | Nature Publishing Group, 2024 |
Medientyp: | academicJournal |
ISSN: | 2041-4889 (print) ; 0246-5434 (print) |
DOI: | 10.1038/s41419-024-06700-y |
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