RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair.
Cell Death Dis
; 15(5): 321, 2024 May 08.
Article
em En
| MEDLINE
| ID: mdl-38719812
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Acetilglucosamina
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Antígeno Nuclear de Célula em Proliferação
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Ubiquitina-Proteína Ligases
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Proteínas de Ligação a DNA
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Rad51 Recombinase
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Reparo de DNA por Recombinação
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article