The transcription process in eukaryotic cells is controlled by the C-terminal domain of RNA polymerase II through its post-translational modification states. However enzymes that recognize the same phosphorylation site in CTD can lead to different transcriptional outcomes. To address the central question that how gene-specific regulation was achieved by CTD regulatory enzymes; we investigate the structure function mechanism of Scp, a human CTD Ser5 phosphatase that functions as a co-repressor for neuronal gene expression. By comparing gene-specific CTD phosphatase Scp, to general-transcription CTD phosphatase Ssu72, we will test two different yet not mutually exclusive hypotheses to explain the differentiated transcription outcomes: molecular targeting and gene-specific CTD code. Finally, we will identify neuronal genes that are subject to Scp regulation and develop chemical tools to investigate the gene expression cascade during neurogenesis. The research breaks new ground in understanding CTD-directed transcription regulation. The chemical compounds developed in this study will become powerful tools to understand the biological mechanism of neuronal stem cell differentiation. Finally, the study of Scp-directed gene silencing in various cell types pave the way to establish if Scp can be a valid drug target for neurodegenerative diseases such as Alzheimer's.

Public Health Relevance

In this proposal, we target a human neuronal silencing protein to promote neuron regeneration. We investigate the molecular mechanisms for the regulation of this enzyme in order to achieve selective inactivation to direct neurogenesis. The compounds developed in this research will become powerful tool to study neuron development and eventually greatly benefit patients with neurodegenerative diseases such as Alzheimer's.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function E Study Section (MSFE)
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Barski, Oleg
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University of Texas Austin
Schools of Arts and Sciences
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Burkholder, Nathaniel Tate; Mayfield, Joshua E; Yu, Xiaohua et al. (2018) Phosphatase activity of small C-terminal domain phosphatase 1 (SCP1) controls the stability of the key neuronal regulator RE1-silencing transcription factor (REST). J Biol Chem 293:16851-16861
Irani, Seema; Naowarojna, Nathchar; Tang, Yang et al. (2018) Snapshots of C-S Cleavage in Egt2 Reveals Substrate Specificity and Reaction Mechanism. Cell Chem Biol 25:519-529.e4
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Cramer, Shira L; Saha, Achinto; Liu, Jinyun et al. (2017) Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat Med 23:120-127
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Yan, Wupeng; Stone, Everett; Zhang, Yan Jessie (2017) Structural Snapshots of an Engineered Cystathionine-?-lyase Reveal the Critical Role of Electrostatic Interactions in the Active Site. Biochemistry 56:876-885
Gibbs, Eric B; Lu, Feiyue; Portz, Bede et al. (2017) Phosphorylation induces sequence-specific conformational switches in the RNA polymerase II C-terminal domain. Nat Commun 8:15233
Portz, Bede; Lu, Feiyue; Gibbs, Eric B et al. (2017) Structural heterogeneity in the intrinsically disordered RNA polymerase II C-terminal domain. Nat Commun 8:15231
Irani, Seema; Yogesha, S D; Mayfield, Joshua et al. (2016) Structure of Saccharomyces cerevisiae Rtr1 reveals an active site for an atypical phosphatase. Sci Signal 9:ra24
Li, Wenzong; Irani, Seema; Crutchfield, Amanda et al. (2016) Intramolecular Cleavage of the hASRGL1 Homodimer Occurs in Two Stages. Biochemistry 55:960-9

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