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MAYFIELD-DISSERTATION-2017.Pdf DISCLAIMER: This document does not meet current format guidelines Graduate School at the The University of Texas at Austin. of the It has been published for informational use only. Copyright by Joshua Edward Mayfield 2017 The Dissertation Committee for Joshua Edward Mayfield Certifies that this is the approved version of the following dissertation: POST-TRANSLATIONAL MODIFICATION OF THE C-TERMINAL DOMAIN OF RNA POLYMERASE II: IDENTIFICATION AND CROSS TALK Committee: Yan Zhang, Supervisor Jennifer S. Brodbelt Marvin L. Hackert Rick Russell Arlen W. Johnson POST-TRANSLATIONAL MODIFICATION OF THE C-TERMINAL DOMAIN OF RNA POLYMERASE II: IDENTIFICATION AND CROSS TALK by Joshua Edward Mayfield Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin August 2017 Acknowledgements Much of the work presented in this dissertation was the result of extensive collaboration with several wonderful groups. The data presented in Chapter 2 would not have been possible but for the aid of Shuang Fan and their advisor Felicia Etzkorn for their organic chemistry and peptide synthesis expertise, Shuo Wei from Kun Ping Lu’s lab for providing shRNA treated HeLa cell material, Bing Li for RNA polymerase II substrate and comments on the manuscript, and Andy Ellington for his extensive commentary and guidance in generating the manuscript. The data in Chapter 3 and subsequent investigations presented in Chapter 4 would not have been possible if not for the tireless effort of members of Jennifer Brodbelt’s group: Michelle Robinson, Victoria Cotham, Rachel Mehaffey, and Joe Cannon who gathered and interpreted mass spectrometry data. I must extend a special acknowledgement to Jennifer Brodbelt herself for her continual support and chemical perspective throughout this collaboration and my graduate career. Finally, I must extend my greatest thanks to my mentor Yan “Jessie” Zhang who has constantly supported me and positioned me alongside a wonderful team of scientists. ABSTRACT: POST-TRANSLATIONAL MODIFICATION OF THE C-TERMINAL DOMAIN OF RNA POLYMERASE II: IDENTIFICATION AND CROSS TALK Joshua Edward Mayfield, Ph.D. The University of Texas at Austin, 2017 Supervisor: Yan Zhang RNA polymerase II is a highly regulated protein complex that transcribes all protein coding mRNA and many non-coding RNAs. A key mechanism that facilitates its activity is post-translational modification of the carboxyl-terminal domain of RNA polymerase II (CTD). This unstructured domain is conserved throughout eukaryotes and composed of repeats of the consensus amino acid heptad Tyr1-Ser2-Pro3-Thr4-Ser5- Pro6-Ser7. This domain acts as a platform for the recruitment of transcriptional regulators that specifically recognize post-translational modification states of the CTD. The majority of our understanding of CTD modification comes from the use of phospho- specific antibodies, which provide identity and abundance information but give only low- resolution information for how these marks co-exist and interact at the molecular level. During my graduate work I sought to utilize the tools of chemical biology to investigate CTD modification in high resolution. Using a combination of chemical tools, analytical chemistry, and molecular biology I studied CTD modification in extremely high resolution. This work reveals the existence of interactions between CTD modifications, i the influence of CTD sequence divergence on modification events, and presents initial data to support a role for previously encoded modifications to direct subsequent modification events. ii Table of Contents LIST OF TABLES VII LIST OF FIGURES VIII CHAPTER 1: THE CTD CODE. 1 Abstract ................................................................................................................... 1 1.1 Transcription in Prokaryotic and Eukaryotic Systems ................................... 2 1.2 RNA Polymerase II: Transcription Cycle ......................................................... 5 1.2.1 Initiation. ............................................................................................... 5 1.2.2 Elongation. ............................................................................................ 7 1.2.3 Termination. .......................................................................................... 8 1.2.4 Transcription cycle and CTD. ............................................................. 10 1.3 The carboxyl-terminal domain of RNA polymerase II & CTD Code ............. 10 1.3.1 Cycle of CTD phosphorylation. .......................................................... 11 1.3.2 Contribution of different CTD phosphorylation marks. ...................... 13 1.3.3 CTD kinases, writers of the code. ....................................................... 16 1.3.4 CTD phosphatases: Erasers of the code. ............................................. 17 1.3.5 Prolyl isomerases: Modifiers of the code. ........................................... 24 1.4 Chemical Biology to Decipher the CTD Code ................................................ 26 1.5 References ....................................................................................................... 28 CHAPTER 2: CHEMICAL TOOLS TO INVESTIGATE PROLINE ISOMERIZATION AND DEPHOSPHORYLATION IN THE CTD CODE. 40 Abstract ................................................................................................................. 40 2.1 Introduction ..................................................................................................... 41 2.2 Results and Discussion .................................................................................... 43 2.2.1 Synthetic CTD peptidomimetic analogues incorporating cis and trans- locked isosteres. .................................................................................. 43 iii 2.2.2 Ssu72 is a cis-specific CTD Ser5 phosphatase. ................................... 45 2.2.3 Scps strongly favor trans-proline as substrate. .................................... 49 2.2.4 Fcp1 is a trans-preferred phosphatase. ................................................ 53 2.2.5 Prolyl isomerase Pin1 does not alter the apparent phosphatase activity of Fcp1. .................................................................................................... 56 2.2.6 In vitro reconstruction of Pin1 mediates Ssu72 enhancement in full length CTD. .................................................................................................... 58 2.2.7 Prolyl isomerase activity regulates cis-specific CTD phosphatase in the cell. ...................................................................................................... 61 2.3 Conclusion and Perspective ............................................................................ 63 2.4 Materials and Methods .................................................................................... 67 2.4.1 Antibodies and reagents ...................................................................... 67 2.4.2 General synthesis and characterization of chemical tools. .................. 67 2.4.3 Protein expression and purification. .................................................... 68 2.4.4 Crystallization and crystal soaking with peptidomimetic compounds.70 2.4.5 Data collection and structure determination. ....................................... 70 2.4.6 Malachite green assay and analysis. .................................................... 71 2.4.7 Fcp1/Pin1 coupled assay and analysis. ............................................... 72 2.4.8 In vitro reconstruction of Pin1 mediated Ssu72 enhancement. ........... 72 2.4.9 Establishment of shPin1 stable cell lines. ........................................... 73 2.4.10 Immunoblotting ................................................................................. 74 2.5 References ....................................................................................................... 75 CHAPTER 3: ULTRAVIOLET PHOTODISSOCIATION MASS SPECTROMETRY TO MAP PHOSPHORYLATION ALONG RNA POLYMERASE II CTD. 79 Abstract ................................................................................................................. 79 3.1 Introduction ..................................................................................................... 80 3.2 Results and Discussion .................................................................................... 83 3.2.1 Analysis of Saccharomyces cerevisiae CTD. ..................................... 83 3.2.2 Analysis of Drosophila melanogaster CTD ........................................ 92 iv 3.2.3 Tyrosine 1 is required for CTD phosphorylation by Erk2 and other CTD kinases. .............................................................................................. 107 3.2.4 Tyrosine 1 limits the addition of phosphates to GST-CTD substrate.108 3.3 Conclusion and Perspective .......................................................................... 110 3.4 Materials and Methods .................................................................................. 112 3.4.1 Materials. ........................................................................................... 112 3.4.2 Protein expression and purification. .................................................. 112 3.4.3 Kinase treatment of GST-CTD constructs. ....................................... 114 3.4.4 Sample preparation for mass spectrometry
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