Nutrient-driven <i>O</i>-GlcNAc cycling – think globally but act locally

Harwood, Katryn R.; Hanover, John A.

doi:10.1242/jcs.113233

Cited by 57 publications

(57 citation statements)

References 141 publications

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“…All percents are the % of pol II peaks either at promoters or in gene bodies. by nutrient flux, as glucose, glutamine, acetyl CoA, and UTP are all necessary for UDP-GlcNAc biosynthesis (35,67). It is likely though that the UDP-GlcNAc is not the only component of the nutrient-sensing mechanism.…”

Section: Tablementioning

confidence: 99%

O-GlcNAcase Is an RNA Polymerase II Elongation Factor Coupled to Pausing Factors SPT5 and TIF1β

Resto

Kim

Fernandez

et al. 2016

Journal of Biological Chemistry

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We describe here the identification and functional characterization of the enzyme O-GlcNAcase (OGA) as an RNA polymerase II elongation factor. Using in vitro transcription elongation assays, we show that OGA activity is required for elongation in a crude nuclear extract system, whereas in a purified system devoid of OGA the addition of rOGA inhibited elongation. Furthermore, OGA is physically associated with the known RNA polymerase II (pol II) pausing/elongation factors SPT5 and TRIM28-KAP1-TIF1␤, and a purified OGA-SPT5-TIF1␤ complex has elongation properties. Lastly, ChIP-seq experiments show that OGA maps to the transcriptional start site/5 ends of genes, showing considerable overlap with RNA pol II, SPT5, TRIM28-KAP1-TIF1␤, and O-GlcNAc itself. These data all point to OGA as a component of the RNA pol II elongation machinery regulating elongation genome-wide. Our results add a novel and unexpected dimension to the regulation of elongation by the insertion of O-GlcNAc cycling into the pol II elongation regulatory dynamics.RNA polymerase II is the species of polymerase that transcribes the protein-coding genes in the cell. Largely based on in vitro transcription data and bacterial transcriptional regulation, it was thought that the pathway of transcription initiation was the de novo assembly and recruitment of general factors and pol II 4 into a preinitiation complex at promoters. In other words, transcription was solely controlled by whether initiation occurred or not. However, in the late 1980s, a transcriptionally engaged pol II was found on several genes, located roughly at ϩ50 relative to the transcriptional start site (TSS) (1-3). More recently, genome-wide approaches have shown that paused pol II exists on at least 40% of promoters in the genome (4 -9).These data show that the regulation of elongation is a significant and widespread method by which cells regulate gene expression.Biochemically, the establishment of a paused polymerase requires the recruitment of DSIF and NELF to pol II early in elongation to prevent pol II from productive elongation (10 -13). Release of the paused polymerase is achieved with P-TEFb phosphorylation of DSIF and NELF, ejecting NELF from pol II and converting DSIF into a positive elongation factor (14,15). The more recent discoveries of additional factors likely involved in pause establishment and release include human capping enzyme (16), the TFIIH-associated kinase, CDK7 (17, 18), the TFIIH ERCC3 helicase (19), , Integrator (23,24), ELL (25), TFIIS (26), TRIM28-KAP1-TIF1␤ (27, 28), Top1 (29), SEC (30), PAF complex (31, 32), and Gdown1 (33). The plethora of factors suggests that more complicated dynamics are at play in regulating pausing and elongation. Additionally, it is not clear, and indeed difficult to know, whether all of the factors involved in pol II pausing and elongation have been identified. This difficulty is due mostly to the absence of a human cell-based in vitro transcription system that recapitulates a paused polymerase and with which the full complement of...

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Section: Tablementioning

confidence: 99%

O-GlcNAcase Is an RNA Polymerase II Elongation Factor Coupled to Pausing Factors SPT5 and TIF1β

Resto

Kim

Fernandez

et al. 2016

Journal of Biological Chemistry

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“…The other major O-GlcNAcase isoform has a 14-amino extension that serves to target it to lipid droplets. This O-GlcNAcase isoform is involved in the remodeling of lipid droplet surface proteins by local activation of proteasomes on the lipid droplet surface (38,42). This study suggested a nexus between the regulation of lipid storage and hexosamine signaling through O-GlcNAc cycling (42).…”

mentioning

confidence: 90%

“…The mOGT and sOGT variants contain 9 and 2 TPR, respectively (37). The TPR mediate interaction with a large number of effector proteins that target or regulate OGT (38,39). It is likely that the TPR also serve a scaffolding function, distinct from any role in enzymatic activity (38).…”

Section: The Enzymes Of O-glcnac Cyclingmentioning

confidence: 99%

“…The TPR mediate interaction with a large number of effector proteins that target or regulate OGT (38,39). It is likely that the TPR also serve a scaffolding function, distinct from any role in enzymatic activity (38). All three isoforms share a common catalytic domain with a deep UDP-GlcNAc binding pocket and a groove for target peptide binding (40).…”

Section: The Enzymes Of O-glcnac Cyclingmentioning

confidence: 99%

“…TET proteins were first discovered through their involvement in myeloid leukemia where the TET1 gene, located on chromosome 10, translocated with the H3K4 histone methyltransferase MLL gene on chromosome 11 (68). The TET proteins are a member of a family of dioxygenases that are dependent upon both ␣-ketoglutarate and iron(II) for their activities (38,67,69,70). Nutrient-dependent O-GlcNAcylation does not seem to play a direct role in regulating TET demethylation activity but may influence its nuclear residency (71).…”

Section: O-glcnac and Epigenetic Regulation Of Transcription By The Hmentioning

confidence: 99%

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O-GlcNAc and the Epigenetic Regulation of Gene Expression

Lewis¹,

Hanover

2014

Journal of Biological Chemistry

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127

116

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O-GlcNAcylation is an abundant nutrient-driven modification linked to cellular signaling and regulation of gene expression. Utilizing precursors derived from metabolic flux, O-GlcNAc functions as a homeostatic regulator. The enzymes of O-GlcNAc cycling, OGT and O-GlcNAcase, act in mitochondria, the cytoplasm, and the nucleus in association with epigenetic "writers" and "erasers" of the histone code. Both O-GlcNAc and O-phosphate modify repeats within the RNA polymerase II C-terminal domain (CTD). By communicating with the histone and CTD codes, O-GlcNAc cycling provides a link between cellular metabolic status and the epigenetic machinery. Thus, O-GlcNAcylation is poised to influence transgenerational epigenetic inheritance.Intermediary metabolism, the process by which nutrients are converted into cellular biomass, is an interwoven network of biochemical reactions allowing reproduction, development, and response to the environment. The intermediary metabolic network is highly conserved and includes every cellular process ranging from DNA replication to transcription and translation to enzyme regulation. Epigenetics, the study of how genes may alter phenotypes beyond their ability to genetically encode information, is ultimately linked to intermediary metabolism (1). Many enzymes that participate in epigenetic gene regulation depend upon co-substrates produced by cellular metabolism, thus providing a potential link between metabolism and gene regulation (2). Mitochondria, key players in these metabolic inter-conversions, exhibit a pattern of cytoplasmic inheritance distinct from Mendelian inheritance of genes encoded in the nucleus (3). O-GlcNAcylation is a key integrator of cellular nutritional status and occurs in the nucleus, cytoplasm, and mitochondrion. O-GlcNAc transferase (OGT) 3 utilizes UDP-GlcNAc to catalyze the addition of O-GlcNAc to target proteins. UDP-GlcNAc is the end product of the hexosamine biosynthetic pathway (HSP), a series of enzymatic reactions requiring key metabolites, including glucose, glutamine, ATP, and acetyl-CoA (4). The nutrient-derived precursors render the synthesis of UDP-GlcNAc and subsequent O-GlcNAc addition by OGT nutrient-responsive. The O-GlcNAcase (OGA; MGEA5) removes the O-GlcNAc modification, and evidence suggests that its transcription and activity is highly regulated. Both enzymes of O-GlcNAc cycling contain domains that allow them to bind to epigenetic modifiers (5, 6). As illustrated in Fig. 1, UDP-GlcNAc is central both to the formation of O-GlcNAc but also to the synthesis of membrane and secretory glycoproteins that perform essential roles in extracellular signaling. The intracellular O-GlcNAc modification plays a role in signaling, leading to growth and apoptosis (7-9), metabolism (10, 11), and the cell cycle (12)(13)(14). In addition, O-GlcNAc has been implicated in translation (15), circadian rhythm (16), the establishment of molecular memory in neurons (17), and calmodulinkinase signaling (16). The focus of this review is the role of O-GlcNAc in transcripti...

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The emerging link between O-GlcNAcylation and neurological disorders

et al. 2017

Cell. Mol. Life Sci.

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O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is involved in the regulation of many cellular cascades and neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In the brain, the expression of O-GlcNAcylation is notably heightened, as is that of O-linked N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA), the presence of which is prominent in many regions of neurological importance. Most importantly, O-GlcNAcylation is believed to contribute to the normal functioning of neurons; conversely, its dysregulation participates in the pathogenesis of neurological disorders. In neurodegenerative diseases, O-GlcNAcylation of the brain's key proteins, such as tau and amyloid-β, interacts with their phosphorylation, thereby triggering the formation of neurofibrillary tangles and amyloid plaques. An increase of O-GlcNAcylation by pharmacological intervention prevents neuronal loss. Additionally, O-GlcNAcylation is stress sensitive, and its elevation is cytoprotective. Increased O-GlcNAcylation ameliorated brain damage in victims of both trauma-hemorrhage and stroke. In this review, we summarize the current understanding of O-GlcNAcylation's physiological and pathological roles in the nervous system and provide a foundation for development of a therapeutic strategy for neurological disorders.

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Nutrient-driven O-GlcNAc cycling – think globally but act locally

Cited by 57 publications

References 141 publications

O-GlcNAcase Is an RNA Polymerase II Elongation Factor Coupled to Pausing Factors SPT5 and TIF1β

O-GlcNAcase Is an RNA Polymerase II Elongation Factor Coupled to Pausing Factors SPT5 and TIF1β

O-GlcNAc and the Epigenetic Regulation of Gene Expression

The emerging link between O-GlcNAcylation and neurological disorders

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