The Ess1 prolyl isomerase: Traffic cop of the RNA polymerase II transcription cycle

Hanes, Steven D.

doi:10.1016/j.bbagrm.2014.02.001

Cited by 40 publications

(55 citation statements)

References 223 publications

(330 reference statements)

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“…Pin1 (Ess1 in yeast) is unique among the CTD modification enzymes as it is a prolyl isomerase, converting proline from a predominantly trans-conformation to a cis-conformation that alters the substrate specificity of the CTD (for example, FCP1 requires Pin1 activity for CTD substrate binding) (87). Acetylation by p300 occurs on the lysine residues in the C-terminal half of the CTD (88).…”

Section: Ctd Modifications and Enzymesmentioning

confidence: 99%

O-GlcNAc and the Epigenetic Regulation of Gene Expression

Lewis¹,

Hanover

2014

Journal of Biological Chemistry

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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Section: Ctd Modifications and Enzymesmentioning

confidence: 99%

O-GlcNAc and the Epigenetic Regulation of Gene Expression

Lewis¹,

Hanover

2014

Journal of Biological Chemistry

127

116

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“…All five of the hydroxylated amino acids (Ser 2 , Ser 5 , and Ser 7 as well as Tyr 1 and Thr 4 ) are phosphorylated in mammalian cells (1, 14 -18). Also, both prolines undergo cis-trans isomerization that affects the phosphorylation status of the other residues (19).…”

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confidence: 99%

The Ssu72 Phosphatase Mediates the RNA Polymerase II Initiation-Elongation Transition

Rosado-Lugo¹,

Hampsey

2014

Journal of Biological Chemistry

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Background: Ssu72 is a RNAPII CTD phosphatase; its function in the transcription cycle has not been established. Results: Ssu72 dephosphorylates Ser(P) 5 at the initiation-elongation transition and regulates Ser 2 phosphorylation status. Conclusion: Ssu72 functions at multiple stages of the RNAPII transcription cycle. Significance: Our results correct two previous misconceptions: (i) that Rtr1 is a Ser(P) 5 phosphatase and (ii) that Ssu72 dephosphorylates Ser(P) 5 only during transcription termination.

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“…Unlike SCP1 and many CTD-binding proteins, the catalytic activity of Ssu72 requires the cis rather than the more prevalent trans configuration of the P-Ser5-Pro6 bond in the heptad repeats. Consequently, the Pin1 peptidylprolyl isomerase (Hanes 2014), which preferentially isomerizes this bond, is rate-limiting for Ssu72 activity in vivo (Werner-Allen et al 2011). …”

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confidence: 99%

A gene-specific role for the Ssu72 RNAPII CTD phosphatase in HIV-1 Tat transactivation

et al. 2014

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HIV-1 Tat stimulates transcription elongation by recruiting the P-TEFb (positive transcription elongation factor-b) (CycT1:CDK9) C-terminal domain (CTD) kinase to the HIV-1 promoter. Here we show that Tat transactivation also requires the Ssu72 CTD Ser5P (S5P)-specific phosphatase, which mediates transcription termination and intragenic looping at eukaryotic genes. Importantly, HIV-1 Tat interacts directly with Ssu72 and strongly stimulates its CTD phosphatase activity. We found that Ssu72 is essential for Tat:P-TEFb-mediated phosphorylation of the S5P-CTD in vitro. Interestingly, Ssu72 also stimulates nascent HIV-1 transcription in a phosphatasedependent manner in vivo. Chromatin immunoprecipitation (ChIP) experiments reveal that Ssu72, like P-TEFb and AFF4, is recruited by Tat to the integrated HIV-1 proviral promoter in TNF-a signaling 2D10 T cells and leaves the elongation complex prior to the termination site. ChIP-seq (ChIP combined with deep sequencing) and GROseq (genome-wide nuclear run-on [GRO] combined with deep sequencing) analysis further reveals that Ssu72 predominantly colocalizes with S5P-RNAPII (RNA polymerase II) at promoters in human embryonic stem cells, with a minor peak in the terminator region. A few genes, like NANOG, also have high Ssu72 at the terminator. Ssu72 is not required for transcription at most cellular genes but has a modest effect on cotranscriptional termination. We conclude that Tat alters the cellular function of Ssu72 to stimulate viral gene expression and facilitate the early S5P-S2P transition at the integrated HIV-1 promoter.

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The Ess1 prolyl isomerase: Traffic cop of the RNA polymerase II transcription cycle

Cited by 40 publications

References 223 publications

O-GlcNAc and the Epigenetic Regulation of Gene Expression

O-GlcNAc and the Epigenetic Regulation of Gene Expression

The Ssu72 Phosphatase Mediates the RNA Polymerase II Initiation-Elongation Transition

A gene-specific role for the Ssu72 RNAPII CTD phosphatase in HIV-1 Tat transactivation

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