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Biochemical Society Transactions Apr 2017Cell division (mitosis) and gamete production (meiosis) are fundamental requirements for normal organismal development. The mammalian cell cycle is tightly regulated by... (Review)
Review
Cell division (mitosis) and gamete production (meiosis) are fundamental requirements for normal organismal development. The mammalian cell cycle is tightly regulated by different checkpoints ensuring complete and precise chromosomal segregation and duplication. In recent years, researchers have become increasingly interested in understanding how -GlcNAc regulates the cell cycle. The -GlcNAc post-translation modification is an -glycosidic bond of a single β--acetylglucosamine sugar to serine/threonine residues of intracellular proteins. This modification is sensitive toward changes in nutrient levels in the cellular environment making -GlcNAc a nutrient sensor capable of influencing cell growth and proliferation. Numerous studies have established that O-GlcNAcylation is essential in regulating mitosis and meiosis, while loss of O-GlcNAcylation is lethal in growing cells. Moreover, aberrant O-GlcNAcylation is linked with cancer and chromosomal segregation errors. In this review, we will discuss how -GlcNAc controls different aspects of the cell cycle with a particular emphasis on mitosis and meiosis.
Topics: Acetylglucosamine; Acylation; Animals; Cell Proliferation; Humans; Meiosis; Mitosis; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Proteins
PubMed: 28408472
DOI: 10.1042/BST20160145 -
Open Biology Sep 2022O-linked--acetylglucosaminylation (O-GlcNAcylation) is a nutrient-sensitive protein modification that alters the structure and function of a wide range of proteins... (Review)
Review
O-linked--acetylglucosaminylation (O-GlcNAcylation) is a nutrient-sensitive protein modification that alters the structure and function of a wide range of proteins involved in diverse cellular processes. Similar to phosphorylation, another protein modification that targets serine and threonine residues, O-GlcNAcylation occupancy on cellular proteins exhibits daily rhythmicity and has been shown to play critical roles in regulating daily rhythms in biology by modifying circadian clock proteins and downstream effectors. We recently reported that daily rhythm in global O-GlcNAcylation observed in tissues is regulated via the integration of circadian and metabolic signals. Significantly, mistimed feeding, which disrupts coordination of these signals, is sufficient to dampen daily O-GlcNAcylation rhythm and is predicted to negatively impact animal biological rhythms and health span. In this review, we provide an overview of published and potential mechanisms by which metabolic and circadian signals regulate hexosamine biosynthetic pathway metabolites and enzymes, as well as O-GlcNAc processing enzymes to shape daily O-GlcNAcylation rhythms. We also discuss the significance of functional interactions between O-GlcNAcylation and other post-translational modifications in regulating biological rhythms. Finally, we highlight organ/tissue-specific cellular processes and molecular pathways that could be modulated by rhythmic O-GlcNAcylation to regulate time-of-day-specific biology.
Topics: Acetylglucosamine; Animals; CLOCK Proteins; Circadian Clocks; Drosophila; Nutrients; Protein Processing, Post-Translational; Proteins
PubMed: 36099933
DOI: 10.1098/rsob.220215 -
Cellular Signalling Feb 2022O-GlcNAcylation is a post-translational modification occurring on serine/threonine residues of nuclear and cytoplasmic proteins, mediated by the enzymes OGT and OGA... (Review)
Review
O-GlcNAcylation is a post-translational modification occurring on serine/threonine residues of nuclear and cytoplasmic proteins, mediated by the enzymes OGT and OGA which catalyze the addition or removal of the UDP-GlcNAc moieties, respectively. Structural changes brought by this modification lead to alternations of protein stability, protein-protein interactions, and phosphorylation. Importantly, O-GlcNAcylation is a nutrient sensor by coupling nutrient sensing with cellular signaling. Elevated levels of OGT and O-GlcNAc have been reported in a variety of cancers and has been linked to regulation of multiple cancer signaling pathways. In this review, we discuss the most recent findings on the role of O-GlcNAcylation as a metabolic sensor in signaling pathways and immune response in cancer.
Topics: Acetylglucosamine; Humans; N-Acetylglucosaminyltransferases; Neoplasms; Phosphorylation; Protein Processing, Post-Translational
PubMed: 34800629
DOI: 10.1016/j.cellsig.2021.110201 -
Experimental Hematology Sep 2021Posttranslational protein modification through addition of the O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed... (Review)
Review
Posttranslational protein modification through addition of the O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed O-GlcNAcylation, is a highly dynamic process conserved throughout eukaryotes. O-GlcNAcylation is reversibly catalyzed by a single pair of enzymes, O-GlcNAc transferase and O-GlcNAcase, and it acts as a fundamental regulator for a wide variety of biological processes including gene expression, cell cycle regulation, metabolism, stress response, cellular signaling, epigenetics, and proteostasis. O-GlcNAcylation is regulated by various intracellular or extracellular cues such as metabolic status, nutrient availability, and stress. Studies over decades have unveiled the profound biological significance of this unique protein modification in normal physiology and pathologic processes of diverse cell types or tissues. In hematopoiesis, recent studies have indicated the essential and pleiotropic roles of O-GlcNAcylation in differentiation, proliferation, and function of hematopoietic cells including T cells, B cells, myeloid progenitors, and hematopoietic stem and progenitor cells. Moreover, aberrant O-GlcNAcylation is implicated in the development of hematologic malignancies with dysregulated epigenetics, metabolism, and gene transcription. Thus, it is now recognized that O-GlcNAcylation is one of the key regulators of normal and malignant hematopoiesis.
Topics: Acetylglucosamine; Animals; Epigenesis, Genetic; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Stem Cells; Humans; Protein Processing, Post-Translational
PubMed: 34302904
DOI: 10.1016/j.exphem.2021.07.003 -
The Journal of Biological Chemistry Nov 2023Cell cycle errors can lead to mutations, chromosomal instability, or death; thus, the precise control of cell cycle progression is essential for viability. The... (Review)
Review
Cell cycle errors can lead to mutations, chromosomal instability, or death; thus, the precise control of cell cycle progression is essential for viability. The nutrient-sensing posttranslational modification, O-GlcNAc, regulates the cell cycle allowing one central control point directing progression of the cell cycle. O-GlcNAc is a single N-acetylglucosamine sugar modification to intracellular proteins that is dynamically added and removed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. These enzymes act as a rheostat to fine-tune protein function in response to a plethora of stimuli from nutrients to hormones. O-GlcNAc modulates mitogenic growth signaling, senses nutrient flux through the hexosamine biosynthetic pathway, and coordinates with other nutrient-sensing enzymes to progress cells through Gap phase 1 (G). At the G/S transition, O-GlcNAc modulates checkpoint control, while in S Phase, O-GlcNAcylation coordinates the replication fork. DNA replication errors activate O-GlcNAcylation to control the function of the tumor-suppressor p53 at Gap Phase 2 (G). Finally, in mitosis (M phase), O-GlcNAc controls M phase progression and the organization of the mitotic spindle and midbody. Critical for M phase control is the interplay between OGT and OGA with mitotic kinases. Importantly, disruptions in OGT and OGA activity induce M phase defects and aneuploidy. These data point to an essential role for the O-GlcNAc rheostat in regulating cell division. In this review, we highlight O-GlcNAc nutrient sensing regulating G, O-GlcNAc control of DNA replication and repair, and finally, O-GlcNAc organization of mitotic progression and spindle dynamics.
Topics: Acetylglucosamine; Acetylglucosaminidase; Mitosis; Mutation; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Signal Transduction; Humans; Animals
PubMed: 37820866
DOI: 10.1016/j.jbc.2023.105330 -
Biochemical Society Transactions Aug 2017The endogenous circadian clock is a key regulator of daily metabolic processes. On the other hand, circadian clocks in a broad range of tissues can be tuned by extrinsic... (Review)
Review
The endogenous circadian clock is a key regulator of daily metabolic processes. On the other hand, circadian clocks in a broad range of tissues can be tuned by extrinsic and intrinsic metabolic cues. The bidirectional interaction between circadian clocks and metabolism involves both transcriptional and post-translational mechanisms. Nuclear receptors exemplify the transcriptional programs that couple molecular clocks to metabolism. The post-translational modifications of the core clock machinery are known to play a key role in metabolic entrainment of circadian clocks. O-linked -acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is a key mediator of metabolic response to nutrient availability. This review highlights our current understanding of the role of protein O-GlcNAcylation in mediating metabolic input and output of the circadian clock.
Topics: Acetylglucosamine; Animals; Appetite Regulation; Circadian Clocks; Circadian Rhythm Signaling Peptides and Proteins; Energy Intake; Energy Metabolism; Humans; Models, Biological; Nerve Tissue Proteins; Protein Processing, Post-Translational; Suprachiasmatic Nucleus Neurons
PubMed: 28673939
DOI: 10.1042/BST20160183 -
ACS Chemical Biology Feb 2017O-GlcNAcylation is the modification of serine and threonine residues with β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. This dynamic modification is... (Review)
Review
O-GlcNAcylation is the modification of serine and threonine residues with β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. This dynamic modification is attached by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA) and is a critical regulator of various cellular processes. Furthermore, O-GlcNAcylation is dysregulated in many diseases, such as diabetes, cancer, and Alzheimer's disease. However, the precise role of this modification and its cycling enzymes (OGT and OGA) in normal and disease states remains elusive. This is partially due to the difficulty in studying O-GlcNAcylation with traditional genetic and biochemical techniques. In this review, we will summarize recent progress in chemical approaches to overcome these obstacles. We will cover new inhibitors of OGT and OGA, advances in metabolic labeling and cellular imaging, synthetic approaches to access homogeneous O-GlcNAcylated proteins, and cross-linking methods to identify O-GlcNAc-protein interactions. We will also discuss remaining gaps in our toolbox for studying O-GlcNAcylation and questions of high interest that are yet to be answered.
Topics: Acetylglucosamine; Glycosyltransferases; Mass Spectrometry; Microscopy, Fluorescence; Molecular Probes; Proteins
PubMed: 28055183
DOI: 10.1021/acschembio.6b01065 -
Current Opinion in Structural Biology Jun 2021O-GlcNAcylation is an enzymatic post-translational modification occurring in hundreds of protein substrates. This modification occurs through the addition of the... (Review)
Review
O-GlcNAcylation is an enzymatic post-translational modification occurring in hundreds of protein substrates. This modification occurs through the addition of the monosaccharide N-acetylglucosamine to serine and threonine residues on intracellular proteins in the cytosol, nucleus, and mitochondria. As a highly dynamic form of modification, changes in O-GlcNAc levels coincide with alterations in metabolic state, the presence of stressors, and cellular health. At the protein level, the consequences of the sugar modification can vary, thus necessitating biochemical investigations on protein-specific and site-specific effects. To this end, enzymatic and chemical methods to 'encode' the modification have been developed and the utilization of these synthetic glycopeptides and glycoproteins has since been instrumental in the discovery of the mechanisms by which O-GlcNAcylation can affect a diverse array of biological processes.
Topics: Acetylglucosamine; Glycoproteins; Peptides; Protein Processing, Post-Translational
PubMed: 33434850
DOI: 10.1016/j.sbi.2020.12.005 -
Journal of Molecular Cell Biology Feb 2023O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a highly dynamic and widespread post-translational modification (PTM) that regulates the activity, subcellular... (Review)
Review
O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a highly dynamic and widespread post-translational modification (PTM) that regulates the activity, subcellular localization, and stability of target proteins. O-GlcNAcylation is a reversible PTM controlled by two cycling enzymes: O-linked N-acetylglucosamine transferase and O-GlcNAcase. Emerging evidence indicates that O-GlcNAcylation plays critical roles in innate immunity, inflammatory signaling, and cancer development. O-GlcNAcylation usually occurs on serine/threonine residues, where it interacts with other PTMs, such as phosphorylation. Thus, it likely has a broad regulatory scope. This review discusses the recent research advances regarding the regulatory roles of O-GlcNAcylation in innate immunity and inflammation. A more comprehensive understanding of O-GlcNAcylation could help to optimize therapeutic strategies regarding inflammatory diseases and cancer.
Topics: Humans; Protein Processing, Post-Translational; Phosphorylation; Neoplasms; Immunity, Innate; Inflammation; Acetylglucosamine
PubMed: 36473120
DOI: 10.1093/jmcb/mjac065 -
International Journal of Molecular... Aug 2019Chronic, low‑grade inflammation associated with obesity and diabetes result from the infiltration of adipose and vascular tissue by immune cells and contributes to... (Review)
Review
Chronic, low‑grade inflammation associated with obesity and diabetes result from the infiltration of adipose and vascular tissue by immune cells and contributes to cardiovascular complications. Despite an incomplete understanding of the mechanistic underpinnings of immune cell differentiation and inflammation, O‑GlcNAcylation, the addition of O‑linked N‑acetylglucosamine (O‑GlcNAc) to cytoplasmic, nuclear and mitochondrial proteins by the two cycling enzymes, the O‑linked N‑acetylglucosamine transferase (OGT) and the O‑GlcNAcase (OGA), may contribute to fine‑tune immunity and inflammation in both physiological and pathological conditions. Early studies have indicated that O‑GlcNAcylation of proteins play a pro‑inflammatory role in diabetes and insulin resistance, whereas subsequent studies have demonstrated that this post‑translational modification could also be protective against acute injuries. These studies suggest that diverse types of insults result in dynamic changes to O‑GlcNAcylation patterns, which fluctuate with cellular metabolism to promote or inhibit inflammation. In this review, the current understanding of O‑GlcNAcylation and its adaptive modulation in immune and inflammatory responses is summarized.
Topics: Acetylglucosamine; Animals; Humans; Immunity; Inflammation; N-Acetylglucosaminyltransferases; Proteins; beta-N-Acetylhexosaminidases
PubMed: 31198979
DOI: 10.3892/ijmm.2019.4238