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The Role Of The Ctd Phosphatase Rtr1 And Post Translational Modifications In Regulation Of Rna Polymerase Ii
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Book Synopsis The Role of the CTD Phosphatase Rtr1 and Post-translational Modifications in Regulation of RNA Polymerase II by : Mary L. Cox
Download or read book The Role of the CTD Phosphatase Rtr1 and Post-translational Modifications in Regulation of RNA Polymerase II written by Mary L. Cox and published by . This book was released on 2013 with total page 186 pages. Available in PDF, EPUB and Kindle. Book excerpt: RNA polymerase II (RNAPII) is regulated by multiple modifications to the C-terminal domain (CTD) of the largest subunit, Rpb1. This study has focused on the relationship between hyperphosphorylation of the CTD and RNAPII turnover and proteolytic degradation as well as post-translational modifications of the globular core of RNAPII. Following tandem affinity purification, western blot analysis showed that MG132 treated RTR1 ERG6 deletion yeast cells have accumulation of total RNAPII and in particular, the hyperphosphorylated form of the protein complex. In addition, proteomic studies using MuDPIT have revealed increased interaction between proteins of the ubiquitin-proteasome degradation system in the mutant MG132 treated yeast cells as well as potential ubiquitin and phosphorylation sites in RNAPII subunits, Rpb6 and Rpb1, respectively. A novel Rpb1 phosphorylation site, T1471-P, is located in the linker region between the CTD and globular domain of Rpb1 and will be the focus of future studies to determine biological significance of this post-translational modification.
Book Synopsis Mechanisms of Recruitment of the CTD Phosphatase Rtr1 to RNA Polymerase II by : Michael J. Berna (Sr.)
Download or read book Mechanisms of Recruitment of the CTD Phosphatase Rtr1 to RNA Polymerase II written by Michael J. Berna (Sr.) and published by . This book was released on 2012 with total page 166 pages. Available in PDF, EPUB and Kindle. Book excerpt: The C-terminal domain (CTD) of the RNA polymerase II (RNAPII) subunit Rpb1 must exist in a hypophosphorylated state prior to forming a competent transcription initiation complex. However, during transcription, specific kinases and phosphatases act on the RNAPII CTD to regulate its phosphorylation state, which serves to recruit sequence-specific and general transcription factors at the appropriate stage of transcription. A key phosphatase involved in this process, Rtr1 (Regulator of Transcription 1), was shown to regulate a key step important for transcription elongation and termination. Although the role that Rtr1 plays in regulating RNAPII transcription has been described, the mechanism involved in the recruitment of Rtr1 to RNAPII during transcription has not been elucidated in yeast. Consequently, the present work utilized both affinity purification schemes in Saccharomyces cerevisiae and mass spectrometry to identify key Rtr1-interacting proteins and post-translational modifications that potentially play a role in recruiting Rtr1 to RNAPII. In addition to RNAPII subunits, which were the most consistently enriched Rtr1-interacting proteins, seven proteins were identified that are potentially involved in Rtr1 recruitment. These included PAF complex subunits (Cdc73, Ctr9, Leo1), the heat shock protein Hsc82, the GTPase Npa3, the ATPase Rpt6, and Spn1. Indirect evidence was also uncovered that implicates that the CTDK-I complex, a kinase involved in RNAPII CTD phosphorylation, is important in facilitating interactions between Rtr1, RNAPII, and select transcription factors. Additionally, a putative phosphorylation site was identified on Ser217 of Rtr1 that may also play a role in its recruitment to RNAPII during transcription.
Book Synopsis Post-translational Modification of the C-terminal Domain of RNA Polymerase II by : Joshua Edward Mayfield
Download or read book Post-translational Modification of the C-terminal Domain of RNA Polymerase II written by Joshua Edward Mayfield and published by . This book was released on 2017 with total page 336 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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, 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
Book Synopsis Regulation of RNA Polymerase II CTD Phosphatase in S. Cerevisiae by : Susanne Jutta Hoheisel
Download or read book Regulation of RNA Polymerase II CTD Phosphatase in S. Cerevisiae written by Susanne Jutta Hoheisel and published by . This book was released on 2005 with total page 328 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis RNA Polymerase II Controls Transcription Dynamics by :
Download or read book RNA Polymerase II Controls Transcription Dynamics written by and published by . This book was released on 2013 with total page 261 pages. Available in PDF, EPUB and Kindle. Book excerpt: The C-terminal domain (CTD) of RNA polymerase II (Pol II) consists of conserved heptapeptide repeats that are subject to sequential waves of posttranslational modifications during specific stages of the transcription cycle. These patterned modifications have led to the postulation of the CTD code hypothesis, where stage-specific patterns define a spatiotemporal code that is recognized by the appropriate interacting partners. This thesis summarizes our efforts to define the CTD code, identify the writers and erasers, and explore the function of the code during transcription. We examined the genome-wide distributions of the phospho-serine modifications. We found unique profile clusters for the "early" serine 5 phosphorylation (Ser5-P), the "mid" serine 7 phosphorylation (Ser7-P), and the "late" serine 2 phosphorylation (Ser2-P). We also identified gene class-specific patterns and find widespread co-occurrence of the CTD marks. These phosphorylation marks are placed by an array of phospho-serine kinases. We identified Kin28 (CDK7) as a Ser7-P kinase, and specific inhibition of Kin28 caused a significant decrease in Ser7-P levels at promoters. However, the promoter-distal Ser7-P marks are not remnants of early phosphorylation by Kin28. Instead, we find that Bur1 (CDK9) is positioned to phosphorylate Ser7 within the coding regions. Next, we investigated the phosphatases that erase the CTD code. The importance of these enzymes is emphasized by our observation that an inability to remove Ser7-P marks is lethal. We identified Ssu72 as a Ser7-P phosphatase, and inactivation of Ssu72 triggers a drastic remodeling of Ser7-P distributions across protein-coding and non-coding genes. Furthermore, we report that removal of all phospho-CTD marks during transcription termination is mechanistically coupled. An inability to remove these marks prevents Pol II from terminating efficiently at both gene classes and also impedes proper transcription initiation. Interestingly, Ssu72 seems to be enriched within introns, peaking at the 3' splice site. Interestingly, we do not find polymerase pausing at the 3' splice site or at the terminal exons, as has been previously reported. Instead, we believe Ssu72 may be involved in facilitating the cotranscriptional recruitment of splicing factors by establishing a chromatin state accommodating to splicing.
Book Synopsis The Role of RNA Polymerase II Phosphorylation in the Early Stages of Transcription by : Jonathan Donald Chesnut
Download or read book The Role of RNA Polymerase II Phosphorylation in the Early Stages of Transcription written by Jonathan Donald Chesnut and published by . This book was released on 1994 with total page 280 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Dennis Magee written by and published by . This book was released on with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Studies on the Transcriptional Regulation by Human RNA Polymerase II Complexes and the CTD-phosphatase by : Helen Cho
Download or read book Studies on the Transcriptional Regulation by Human RNA Polymerase II Complexes and the CTD-phosphatase written by Helen Cho and published by . This book was released on 1999 with total page 346 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Role of the RNA Polymerase II CTD-phosphatase FCP1 in Transcription by : Paolo Licciardo
Download or read book Role of the RNA Polymerase II CTD-phosphatase FCP1 in Transcription written by Paolo Licciardo and published by . This book was released on 2003 with total page 215 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Structural Heterogeneity in the RNA Polymerase II C-Terminal Domain by : Bede Portz
Download or read book Structural Heterogeneity in the RNA Polymerase II C-Terminal Domain written by Bede Portz and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: RNA polymerase II contains a repetitive and intrinsically disordered C-Terminal Domain (CTD) composed of heptad repeats of the consensus sequence YSPTSPS. The CTD can be heavily phosphorylated and serves as a scaffold, interacting with factors involved in transcription initiation, elongation, termination, RNA processing and chromatin modification. Despite its role as a nexus of eukaryotic gene regulation, the structure of the CTD and the structural implications of CTD phosphorylation, are poorly understood. Additionally, there is an increasing awareness of the importance of intrinsically disordered proteins (IDPs) that function without adopting a stably folded structure. Here I present a biophysical and biochemical interrogation of the structure of the full-length CTD of D. melanogaster, which I conclude is a compact random coil. I find that the repetitive CTD is structurally heterogeneous as evidenced by a discontinuous pattern of cutting in limited proteolysis assays. Small Angle X-Ray scattering (SAXS) is a method ideally suited for the structural interrogation of large IDPs and can be employed to measure the size of a protein and to monitor structural changes in response to post-translational modification. Using SAXS I determined that phosphorylation by the kinase P-TEFb caused an increase in CTD radius and stiffness. Limited proteolysis of the phosphorylated CTD showed these gross structural changes are accompanied by increased protease accessibility and an alteration in relative protease accessibility across the length of the CTD.Additionally, we show that the human CTD is also structurally heterogeneous and able to substitute for the Drosophila melanogaster CTD in supporting the development of flies to adulthood. These finding implicate conserved structural organization, not a precise array of heptad motifs, as important to CTD function.The CTD is attached to the catalytic core of Pol II via a linker. I show that this linker is more compact than the CTD repeats and serves as an independent structural unit. The phosphorylated linker-CTD remains flexible relative to the phosphorylated CTD alone. Together, these results support a mechanism by which phosphorylation reduces the conformational entropy of the CTD, generating a more binding competent dock for CTD:protein interactions, with the linker region maintaining the ability of CTD bound factors to sample the 3-dimensional space which may be required for RNA processing and histone modification.The data described herein represent the most thorough structural characterization to date of the full length CTD on the global and local scales, examining both the overall size and local structural organization of the CTD. These studies establish the Drosophila CTD as an attractive model for the biophysical, biochemical and genetic interrogation of the structure and function of the CTD from a developmentally complex organism.
Book Synopsis Structural Basis of RNA Polymerase II C-terminal Domain Kinase and Phosphatase Specificity and Their Impact on Transcriptional Regulation by : Nathaniel Tate Burkholder
Download or read book Structural Basis of RNA Polymerase II C-terminal Domain Kinase and Phosphatase Specificity and Their Impact on Transcriptional Regulation written by Nathaniel Tate Burkholder and published by . This book was released on 2019 with total page 292 pages. Available in PDF, EPUB and Kindle. Book excerpt: Transcription from a most basic perspective is the process of generating strands of RNA from DNA templates. However, in order to control when, where, and how much of specific RNAs are made, cells have evolved vast arrays of transcriptional regulatory mechanisms that allow for extensive differentiation and formation of complex traits. One of the unique and most important mechanisms of transcriptional regulation in eukaryotic cells is the reversible phosphorylation of the RNA polymerase II C-terminal domain (RNAPII CTD). The CTD contains heptad repeats composed of the consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 and all of the non-proline sites are phosphorylated in cells. The human CTD contains 52 repeats where the first 26 proximal heptads are mostly consensus sequence whereas the last 26 distal heptads contain several variations primarily at the Ser7 position. In Chapter 2, I describe how these variations and their modifications alter the phosphorylation of Tyr1 sites by using a combination of biochemical assays and mass spectrometry. Data presented in this chapter reveal how a conserved positively charged pocket in tyrosine kinases likely mediates the interaction residues in the Ser7 position and can potentially affect in vivo Tyr1 phospho-patterning. Futhermore, in Chapter 3 I describe the methodology behind synthesis and testing of cis/trans-locked Ser-Pro CTD peptides for understanding the role of prolyl isomerization on CTD regulation. We used these tools to determine the specificity of several CTD phosphatases, which revealed how the Ser5 phosphatase SSU72 structurally prefers the cis- over the trans-configuration of the phosphorylated Ser5-Pro6 motif. Among the phosphatases discovered to dephosphorylate the CTD, the family of SCP phosphatases seem to be more involved in regulating transcription through dephosphorylation of a different protein called the RE-1 silencing transcription factor (REST). REST is a major silencer of neuronal gene expression in non-neuronal cells which helps prevent development of improper neuronal phenotypes. Abnormally high protein levels of REST have been found in subsets of glioblastoma isolates which likely contributes to their oncogenesis and resistance of chemotherapeutics. SCP1 upregulates REST protein levels through dephosphorylating two degron sites that normally promote rapid turnover of REST, making it a potential drug target for glioblastomas in future studies. In Chapter 4, we show structurally how SCP1 recognizes these REST phosphorylation sites through complex x-ray crystallography. Data presented in this chapter reveal SCP1 specificity for each REST site and how SCP1 activity towards both of them promote REST gene silencing function
Book Synopsis Role of RNA Polymerase II Pausing in Transcriptional Regulation of Drosophila Genes by : Thomas Paul O'Brien
Download or read book Role of RNA Polymerase II Pausing in Transcriptional Regulation of Drosophila Genes written by Thomas Paul O'Brien and published by . This book was released on 1994 with total page 252 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Regulation of Human RNA Polymerase II CTD Modifications by : Olʹga Kuznet︠s︡ova
Download or read book Regulation of Human RNA Polymerase II CTD Modifications written by Olʹga Kuznet︠s︡ova and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Phosphatases and Prolyl-isomerase in the Regulation of the C-terminal Domain of Eukaryotic RNA Polymerase II by : Mengmeng Zhang
Download or read book Phosphatases and Prolyl-isomerase in the Regulation of the C-terminal Domain of Eukaryotic RNA Polymerase II written by Mengmeng Zhang and published by . This book was released on 2012 with total page 428 pages. Available in PDF, EPUB and Kindle. Book excerpt: In eukaryotes, the first step of interpreting the genetic information is the transcription of DNA into RNA. For protein-coding genes, such transcription is carried out by RNA polymerase II. A special domain of RNA polymerase II, called the C-terminal domain (CTD), functions as a master controller for the transcription process by providing a platform to recruit regulatory proteins to nascent mRNA (Chapter 1-2). The modifications and conformational states of the CTD, termed the 'CTD code', represent a critical regulatory checkpoint for transcription. The CTD, found only in eukaryotes, consists of 26--52 tandem heptapeptide repeats with the consensus sequence, Tyr1Ser2Pro3Thr4Ser5Pro6Ser--. Phosphorylation of the serines and prolyl isomerization of the prolines represent two major regulatory mechanisms of the CTD. Interestingly, the phosphorylation sites are typically close to prolines, thus the conformation of the adjacent proline could impact the specificity of the corresponding kinases and phosphatases. Understanding how those modifying enzymes recognize and regulate the CTD is important for expanding our knowledge on the transcription regulation and deciphering the 'CTD code'. During my PhD study, I studied the function of CTD phosphatases and prolyl isomerase in the CTD regulation using Scp1, Ssu72 and Pin1 as model regulators. Scp1 and Ssu72 are both Ser5 phosphatases. However, Ssu72 is an essential protein and regulates the global transcription while Scp1 epigenetically silences the expression of specific neuronal genes. Pin1 is a highly conserved phosphorylation-specific prolyl isomerase that recognizes the phospho-Ser/Thr-Pro motif within the CTD as one of its primary substrates in vivo. Among these enzymes, Scp1 is the focal point of this dissertation, as it was studied from different angles, such as enzymatic mechanism (Chapter 3 describes the capture of phospho-aspartyl intermediate of Scp1 as a direct evidence for the proposed two-step mechanism), specific inhibition (Chapter 4 describes the identification and characterization of the first specific inhibitor of Scp1), and its non-active-site contact with the CTD (Chapter 5 describes the structural basis of this contact). These studies are of great importance towards understanding the molecular mechanism of the dephosphorylation process of the CTD by Scp1.
Book Synopsis Structure and Mechanism of the RNA Polymerase II CTD Phosphatase Scp1 and Large-scale Preparation of the RNA Polymerase II-TFIIF Complex by : Tomislav Kamenski
Download or read book Structure and Mechanism of the RNA Polymerase II CTD Phosphatase Scp1 and Large-scale Preparation of the RNA Polymerase II-TFIIF Complex written by Tomislav Kamenski and published by . This book was released on 2006 with total page 218 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis An Investigation of the Regulation of RNA Polymerase II Transcription by : Yanling Zhao
Download or read book An Investigation of the Regulation of RNA Polymerase II Transcription written by Yanling Zhao and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis The Nature of RNA Polymerase II Interactions Mediated by the CTD in the Assembly of Transcription Complexes by : Mona Eunsung Kang
Download or read book The Nature of RNA Polymerase II Interactions Mediated by the CTD in the Assembly of Transcription Complexes written by Mona Eunsung Kang and published by . This book was released on 1995 with total page 304 pages. Available in PDF, EPUB and Kindle. Book excerpt:
