O-GlcNAcylation and chromatin remodeling in mammals: an up-to-date overview

Leturcq, Maïté; Lefebvre, Tony; Vercoutter‐Edouart, Anne‐Sophie

doi:10.1042/bst20160388

Cited by 33 publications

(33 citation statements)

References 103 publications

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“…Global transcriptional responses to OGT and OGA inhibition O-GlcNAc transferase (OGT) dynamically glycosylates numerous chromatin components and transcription factors (Ozcan et al, 2010;Sakabe et al, 2010;Lewis & Hanover, 2014;Leturcq et al, 2017). However, it remains challenging to identify the particular O-GlcNAc substrate(s) that are most functionally important in particular gene expression programs.…”

Section: Resultsmentioning

confidence: 99%

Glycosylation of KEAP1 links nutrient sensing to redox stress signaling

et al. 2017

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O-GlcNAcylation is an essential, nutrient-sensitive post-translational modification, but its biochemical and phenotypic effects remain incompletely understood. To address this question, we investigated the global transcriptional response to perturbations in O-GlcNAcylation. Unexpectedly, many transcriptional effects of O-GlcNAc transferase (OGT) inhibition were due to the activation of NRF2, the master regulator of redox stress tolerance. Moreover, we found that a signature of low OGT activity strongly correlates with NRF2 activation in multiple tumor expression datasets. Guided by this information, we identified KEAP1 (also known as KLHL19), the primary negative regulator of NRF2, as a direct substrate of OGT We show that O-GlcNAcylation of KEAP1 at serine 104 is required for the efficient ubiquitination and degradation of NRF2. Interestingly, O-GlcNAc levels and NRF2 activation co-vary in response to glucose fluctuations, indicating that KEAP1 O-GlcNAcylation links nutrient sensing to downstream stress resistance. Our results reveal a novel regulatory connection between nutrient-sensitive glycosylation and NRF2 signaling and provide a blueprint for future approaches to discover functionally important O-GlcNAcylation events on other KLHL family proteins in various experimental and disease contexts.

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Section: Resultsmentioning

confidence: 99%

Glycosylation of KEAP1 links nutrient sensing to redox stress signaling

et al. 2017

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“…Protein O-GlcNAc modifications are highly dynamic and can be rapidly removed by the hexosaminidase O-GlcNAcase (OGA). Together, OGT and OGA regulate O-GlcNAcylation of thousands of cytosolic, mitochondrial, and nuclear proteins, affecting protein folding, stability, localization, and function (17)(18)(19)(20)(21). In many OGT substrates, residues modified by O-GlcNAcylation are also subject to phosphorylation by Ser/Thr kinases, providing a link between metabolism and diverse types of cell signaling (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

“…In many OGT substrates, residues modified by O-GlcNAcylation are also subject to phosphorylation by Ser/Thr kinases, providing a link between metabolism and diverse types of cell signaling (22)(23)(24). OGT has been implicated in coupling epigenetic regulation to cell metabolism via altered histone modifications (25)(26)(27), regulation of Polycomb group proteins and other chromatin modifiers (21,28,29), and by its binding to and modification of TET DNA demethylases (19,26,30,31).…”

Section: Introductionmentioning

confidence: 99%

O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors

Efimova

Appelbe

Ricco

et al. 2019

Molecular Cancer Research

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The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein posttranslational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double-strand break (DSB) repair and resistance to therapyinduced senescence in cancer cells. We have examined the effects of modulating O-GlcNAcylation on the DNA damage response (DDR) in MCF7 human mammary carcinoma in vitro and in xenograft tumors. Proteomic profiling revealed deregulated DDR pathways in cells with altered O-GlcNAcylation. Promoting protein O-GlcNAc modification by targeting O-GlcNAcase or simply treating animals with GlcNAc protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by blocking O-GlcNAc transferase activity led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DDR, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy. Implications: The finding that the HBP, via its impact on protein O-GlcNAcylation, is a key determinant of the DDR in cancer provides a mechanistic link between metabolic reprogramming, genomic instability, and therapeutic response and suggests novel therapeutic approaches for tumor radiosensitization.

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“…O-GlcNAcylation is now recognized as an important player in epigenetic regulations (12). Looking back through the series of reviews and original articles gathered here, we feel that this Research Topic has been an opportunity for several young researchers to present their first work on this particularly exciting modification.…”

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confidence: 91%