Nutrient-Driven O-GlcNAcylation Controls DNA Damage Repair Signaling and Stem/Progenitor Cell Homeostasis

Na, Hyun-Jin; Akan, Ilhan; Abramowitz, Lara K.; Hanover, John A.

doi:10.1016/j.celrep.2020.107632

Cited by 28 publications

(32 citation statements)

References 60 publications

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“…Upon stimulation, HBP culminates through several steps in the production of UDP-GlcNAc which provides the GlcNAc moiety for protein glycosylation and thus acts as a mechanism of nutrient signaling which impacts various cellular processes [17,18]. Recent studies have started to demonstrate specific roles of protein O-GlcNAcylation in stem cell function during embryogenesis and in postnatal development using both stem cell culture experiments (ESCs and tissue resident adult stem cells) and animal models [19][20][21]. ESCs are pluripotent cells of the inner cell mass of the blastocyst stage embryo.…”

Section: Introductionmentioning

confidence: 99%

Stem cell fate determination through protein O-GlcNAcylation

Sheikh

Emerald

Ansari

2021

Journal of Biological Chemistry

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Embryonic and adult stem cells possess the capability of self-renewal and lineage specific differentiation. The intricate balance between self-renewal and differentiation is governed by developmental signals and cell type specific gene regulatory mechanisms. A perturbed intra/extracellular environment during lineage specification could affect stem cell fate decisions resulting in pathology. Growing evidence demonstrates that metabolic pathways govern epigenetic regulation of gene expression during stem cell fate commitment through the utilization of metabolic intermediates or end products of metabolic pathways as substrates for enzymatic histone/DNA modifications. UDP-GlcNAc is one such metabolite which acts as a substrate for enzymatic mono-glycosylation of various nuclear, cytosolic, and mitochondrial proteins on serine/threonine amino acid residues, a process termed protein O-GlcNAcylation. The levels of GlcNAc inside the cells depend on the nutrient availability, especially glucose. Thus, this metabolic sensor could modulate gene expression through O-GlcNAc modification of histones or other proteins in response to metabolic fluctuations. Herein, we review evidence demonstrating how stem cells couple metabolic inputs to gene regulatory pathways through O-GlcNAc-mediated epigenetic/transcriptional regulatory mechanisms to govern self-renewal and lineage specific differentiation programs. This review will serve as a primer for researchers seeking to better understand how O-GlcNAc influences stemness, and may catalyze the discovery of new stem cell-based therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Stem cell fate determination through protein O-GlcNAcylation

Sheikh

Emerald

Ansari

2021

Journal of Biological Chemistry

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“…Recently, we have reported that stress induces hyper-proliferation, O-GlcNAcylation, and DDR in Drosophila intestinal stem cells (Na et al, 2020). Likewise, genetic elevation of O-GlcNAc by deletion of Oga induced proliferation and DDR in fly intestinal stem cells, mouse embryonic fibroblasts, and mouse ESCs (Na et al, 2020). Previous work had shown that Chk1 phosphorylates OGT, which stabilizes the protein (Li et al, 2017).…”

Section: H2ax and The Dna Damage Responsementioning

confidence: 97%

“…In addition, one report has suggested OGT transfers GlcNAc onto H2AXS139, the same site as γ-phosphorylation (Chen and Yu, 2016). The authors suggest O-GlcNAc inhibits the DDR, though other studies suggest O-GlcNAc activates the DDR pathway (Efimova et al, 2019;Na et al, 2020).…”

Section: H2ax and The Dna Damage Responsementioning

confidence: 99%

“…The elevation of ROS in high glucose conditions may be linked to O-GlcNAc, as inhibition of OGT decreases ROS levels in a dose-dependent manner, and ultimately reduces neural tube defects in embryos of diabetic mice (Kim et al, 2017). Recently, we have reported that stress induces hyper-proliferation, O-GlcNAcylation, and DDR in Drosophila intestinal stem cells (Na et al, 2020). Likewise, genetic elevation of O-GlcNAc by deletion of Oga induced proliferation and DDR in fly intestinal stem cells, mouse embryonic fibroblasts, and mouse ESCs (Na et al, 2020).…”

Section: H2ax and The Dna Damage Responsementioning

confidence: 99%

“…Advances in mass spectrometry technology have uncovered O-GlcNAcylation of histones, and is now widely believed to be part of the "histone code." Studies have also indicated that O-GlcNAc plays a role in histone exchange and is essential for the DNA damage response (Na et al, 2020). Further, OGT has been found in complex with TET proteins, signifying a potential role in DNA demethylation (Chen et al, 2013;Deplus et al, 2013;Vella et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability

et al. 2020

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Cellular identity in multicellular organisms is maintained by characteristic transcriptional networks, nutrient consumption, energy production and metabolite utilization. Integrating these cell-specific programs are epigenetic modifiers, whose activity is often dependent on nutrients and their metabolites to function as substrates and co-factors. Emerging data has highlighted the role of the nutrient-sensing enzyme O-GlcNAc transferase (OGT) as an epigenetic modifier essential in coordinating cellular transcriptional programs and metabolic homeostasis. OGT utilizes the end-product of the hexosamine biosynthetic pathway to modify proteins with O-linked β-D-N-acetylglucosamine (O-GlcNAc). The levels of the modification are held in check by the O-GlcNAcase (OGA). Studies from model organisms and human disease underscore the conserved function these two enzymes of O-GlcNAc cycling play in transcriptional regulation, cellular plasticity and mitochondrial reprogramming. Here, we review these findings and present an integrated view of how O-GlcNAc cycling may contribute to cellular memory and transgenerational inheritance of responses to parental stress. We focus on a rare human genetic disorder where mutant forms of OGT are inherited or acquired de novo. Ongoing analysis of this disorder, OGT- X-linked intellectual disability (OGT-XLID), provides a window into how epigenetic factors linked to O-GlcNAc cycling may influence neurodevelopment.

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A Multilevel Approach to the Causes of Genetic Instability in Stem Cells

González

2022

Handbook of Stem Cell Therapy

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This chapter addresses the genetic instability in stem cells, a central feature that is an important determinant for the safety and effectiveness of cell-based therapies. First, DNA damage response mechanism and the gene network that regulates the DNA integrity homeostasis are revisited, focusing on relationship between genetic integrity and stemness maintenance. Also, several factors have been included that influence genetic instability in vivo, i.e., ROS generation and inflammation, and in vitro regarding cell isolation, culture conditions, i.e., oxygen levels and the use of feeder layers and different carriers, splitting procedures, passage number, etc. Telomere shortening, replicative senescence aneuploidy, and the senescence-associated secretory phenotype are different processes involved in deterioration of stem cells abilities for homing, reparability, and paracrine modulation. Moreover, less effective DNA repair upon senescence increases the propensity of developing tumors for stem cells that is one the main concerns related to genetic instability in stem cells. Nuclear organization and their determinants linked to chromosome aberrations and aneuploidy in stem cells and those epigenetic changes affecting stability are addressed. Differences between adipose, embryonic, and induced pluripotent stem cells are analyzed regarding to their ontogeny, changes in culture, and variation in proliferative capacity and stemness. The effect of reprogramming methods in genetic instability and variation in mutagenicity according to genes utilized for pluripotency induction, i.e., Yamanaka's factors and others, is discussed. Donor-related factors, i.e., age, smoking, and alcohol consumption, comorbidities, i.e., obesity, insulin resistance, diabetes, are mentioned for wide evaluation of genetic instability. The next years must witness consensus protocols that will contribute to control the effects of factors that alter stem cell genetic stability to increase the security and applicability of cell-based therapy.

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Nutrient-Driven O-GlcNAcylation Controls DNA Damage Repair Signaling and Stem/Progenitor Cell Homeostasis

Cited by 28 publications

References 60 publications

Stem cell fate determination through protein O-GlcNAcylation

Stem cell fate determination through protein O-GlcNAcylation

O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability

A Multilevel Approach to the Causes of Genetic Instability in Stem Cells

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