O-GlcNAc transferase is important for homology-directed repair

Ping, Xiaoli; Stark, Jeremy M.

doi:10.1016/j.dnarep.2022.103394

Cited by 9 publications

(5 citation statements)

References 59 publications

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“…Therefore, fine-tune of RAD18 function might be a promising approach for sensitizing cancer cells to genotoxic therapeutic agents. Protein O-GlcNAcylation is emerging as an important and abundant form of covalent modifications that regulate DNA damage repair, and many DDR-associated proteins under O-GlcNAcylation upon DNA damage, including Polη, CtIP and RAD52 [29][30][31]46]. However, the role of RAD18 O-GlcNAcylation still remains unexplored.…”

Section: O-glcnacylation Promotes the Binding Of Rad18 To Ubiquitin A...mentioning

confidence: 99%

“…Moreover, cell cycle kinase CDC7-dependent Ser434 phosphorylation of RAD18 is essential for recruiting Polη to sites of UV-induced DNA damage [28]. Recently, O-Linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) has been reported to localize to DNA lesions and promote the O-GlcNAcylation at serine and threonine residues of DNA repair factors upon UV, CDDP and ionizing radiation (IR) treatment [29][30][31][32][33][34]. Nevertheless, an enigma remains of how O-GlcNAcylation may govern RAD18 during TLS and HR repair.…”

Section: Introductionmentioning

confidence: 99%

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

Ma,

Fu,

Sun

et al. 2024

Cell Death Dis

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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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Section: O-glcnacylation Promotes the Binding Of Rad18 To Ubiquitin A...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ma,

Fu,

Sun

et al. 2024

Cell Death Dis

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“…The critical role of OGT/O-GlcNAc in repairing DNA double-strand break is also observed in breast cancer, where an increase in O-GlcNAc level induces resistance of xenograft tumor against radiation, while inhibition of OGT impairs double-strand break repair and reduces cancer cell growth in vivo ( 140 ). In osteosarcoma, pharmacological and genetic inhibitions of OGT lead to a reduction in DNA double-strand break repair mediated by RAD52-dependent homology recombination, ultimately resulting in cell cycle arrest and reduced cell proliferation ( 141 ).…”

Section: Contributions Of Ogt/o-glcnacylation In Cancermentioning

confidence: 99%

On a sugar high: Role of O-GlcNAcylation in cancer

Le Minh,

Esquea,

Young

et al. 2023

Journal of Biological Chemistry

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“…Currently, O-GlcNAc transferase (OGT) is the only known enzyme in this process affecting cell survival by modulating cell cycle and RAD52 functions. It has been proposed as a novel target in cancer therapies [147,148]. In addition, NEIL3 DNA glycosylase was extensively studied.…”

Section: Dna Damage Repair Modulated By Other Ptmsmentioning

confidence: 99%

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

Xie

Zhou

2023

IJMS

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DNA damage in astronauts induced by cosmic radiation poses a major barrier to human space exploration. Cellular responses and repair of the most lethal DNA double-strand breaks (DSBs) are crucial for genomic integrity and cell survival. Post-translational modifications (PTMs), including phosphorylation, ubiquitylation, and SUMOylation, are among the regulatory factors modulating a delicate balance and choice between predominant DSB repair pathways, such as non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we focused on the engagement of proteins in the DNA damage response (DDR) modulated by phosphorylation and ubiquitylation, including ATM, DNA-PKcs, CtIP, MDM2, and ubiquitin ligases. The involvement and function of acetylation, methylation, PARylation, and their essential proteins were also investigated, providing a repository of candidate targets for DDR regulators. However, there is a lack of radioprotectors in spite of their consideration in the discovery of radiosensitizers. We proposed new perspectives for the research and development of future agents against space radiation by the systematic integration and utilization of evolutionary strategies, including multi-omics analyses, rational computing methods, drug repositioning, and combinations of drugs and targets, which may facilitate the use of radioprotectors in practical applications in human space exploration to combat fatal radiation hazards.

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O-GlcNAc transferase is important for homology-directed repair

Cited by 9 publications

References 59 publications

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

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

On a sugar high: Role of O-GlcNAcylation in cancer

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

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