RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair

作者：Xiaolu Ma, Hui Fu, Chenyi Sun, W.J. Wu, Wenya Hou, Zibin Zhou, Hui Zheng, Yifei Gong, Honglin Wu, Junying Qin, Huiqiang Lou, Jing Li, Tie-Shan Tang, Caixia Guo · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-06700-y · 被引用次数：13 · 研究领域：DNA Repair Mechanisms、Glycosylation and Glycoproteins Research、Cytomegalovirus and herpesvirus research

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.