1. RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair
- Author
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Xiaolu Ma, Hui Fu, Chenyi Sun, Wei Wu, Wenya Hou, Zibin Zhou, Hui Zheng, Yifei Gong, Honglin Wu, Junying Qin, Huiqiang Lou, Jing Li, Tie-Shan Tang, and Caixia Guo
- Subjects
Cytology ,QH573-671 - Abstract
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.
- Published
- 2024
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