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)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Barski, Oleg
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Austin
Schools of Arts and Sciences
United States
Zip Code
Mayfield, Joshua E; Burkholder, Nathaniel T; Zhang, Yan Jessie (2016) Dephosphorylating eukaryotic RNA polymerase II. Biochim Biophys Acta 1864:372-87
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
Wei, Shuo; Kozono, Shingo; Kats, Lev et al. (2015) Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 21:457-66
Mayfield, Joshua E; Fan, Shuang; Wei, Shuo et al. (2015) Chemical Tools To Decipher Regulation of Phosphatases by Proline Isomerization on Eukaryotic RNA Polymerase II. ACS Chem Biol 10:2405-14
Chen, Chun-Hau; Li, Wenzong; Sultana, Rukhsana et al. (2015) Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease. Neurobiol Dis 76:13-23
He, Yantao; Guo, Xing; Yu, Zhi-Hong et al. (2015) A potent and selective inhibitor for the UBLCP1 proteasome phosphatase. Bioorg Med Chem 23:2798-809
Yan, Wupeng; Song, Heng; Song, Fuhang et al. (2015) Endoperoxide formation by an α-ketoglutarate-dependent mononuclear non-haem iron enzyme. Nature 527:539-43
Yogesha, S D; Mayfield, Joshua E; Zhang, Yan (2014) Cross-talk of phosphorylation and prolyl isomerization of the C-terminal domain of RNA Polymerase II. Molecules 19:1481-511
O'Brien, John P; Li, Wenzong; Zhang, Yan et al. (2014) Characterization of native protein complexes using ultraviolet photodissociation mass spectrometry. J Am Chem Soc 136:12920-8