DOCSLIB.ORG

Molecular Basis of Rrn3-Regulated RNA Polymerase I Initiation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Molecular Basis of Rrn3-Regulated RNA Polymerase I Initiation Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig–Maximilians–Universität München Molecular Basis of Rrn3-regulated RNA Polymerase I Initiation Claudia Blattner aus Lörrach 2011 Erklärung Diese Dissertation wurde im Sinne von §13 Abs. 3 bzw. 4 der Promotionsordnung vom 29. Januar 1998 (in der Fassung der sechsten Änderungssatzung vom 16. August 2010) von Herrn Prof. Dr. Patrick Cramer betreut. Ehrenwörtliche Versicherung Diese Dissertation wurde selbstständig, ohne unerlaubte Hilfe erarbeitet. München, am 14.10.2011 Claudia Blattner Dissertation eingereicht am 21.10.2011 1. Gutachter Prof. Patrick Cramer 2. Gutachter Prof. Roland Beckmann Mündliche Prüfung am 05.12.2011 1 Acknowledgements First of all, I would like to thank Patrick who has been a great supervisor and mentor over the last years. Thank you for your constant support and advice, and for sharing your enthusiasm about science. I am very grateful for the opportunity, to do my PhD in this fantastic lab, and to experience this very productive setting but also social atmosphere. I want to extend this acknowledgement not only to the lab, but also to the whole scientific environment I had the chance to work in. This includes the entire Gene Center, with its great and collaborative atmosphere, and extends to the MPI, Martinsried, and the research groups and people involved in the IMPRS-ls program, which provided a great framework for doing research but also getting insight into a broader spectrum of life sciences and to stay in contact with other researchers. In this context, many thanks to Maxi and Hans-Jörg, who coordinated all the workshops and other IMPRS activities I could participate in. I also got a lot of advice and help from people in the lab. I want to thank Alan for the help and training in crystallography, for spending countless hours at the synchrotron with me, explaining, but also having great conversations and drinking whiskey. Many thanks to Rieke for exchanging our experiences and thoughts throughout our PhD time, for being a great and fun roommate at all the retreats, and conferences. Thanks to Elmar for interesting conversations and your enthusiasm about science, Tobi, for explaining and helping most patiently with so many bioinformatic programs. Thank you Jenne, for a lot of help in the lab right from the start until today with various issues, and for your friendship. Many thanks to Jasmin, for endless conversations, for your general advice on labwork and especially for being a great friend. Thanks to Kerstin, Sarah and Fuensanta for enjoyable hikes together, parties, and christmas-cookie sessions. I also would like to thank Claudia for keeping the lab running and being the source of the good atmosphere. Thanks to Stefan Benkert, not only for the yeast fermentation, but also for help with a lot of technical issues. Many thanks to all the others in the lab, who contributed to the great working atmosphere, for a great time not only in the lab, but also apart from working hours, during retreats, beer garden visits and our annual “lab-wiesn”. Also many thanks to my student 2 Sandra, who was a great help in starting the core factor project, I really appreciate your interest and excitement about this work. I thank Thomas Fröhlich for frequent and very helpful masspec protein identification. Further, I would like to acknowledge all the people contributing to the experiments, that made this work successful. This includes my collaboration partners Kristina Lorenzen from the lab of Albert Heck at the University of Utrecht, Franz Herzog from the lab of Ruedi Aebersold at the ETH, Zürich, Gregor Witte from Karl-Peter Hopfner’s lab at the Gene Center, and Andreas Mayer from our lab. Many thanks also to the people from the Beckmann lab, Otto Berninghausen, Charlotte Ungewickell and Thomas Becker who helped me with EM data collection and processing, and patiently answered all my questions, and, of course, Anselm for his help. Finally, I want to thank my parents, who aroused my interest in science and supported and motivated me to make my way, also when things were not easy. And thank you Niklas, for your patience, your support and understanding. 3 Summary Eukaryotic nuclear transcription is carried out by three different Polymerases (Pol), Pol I, Pol II and Pol III. Among these, Pol I is dedicated to transcription of the rRNA, which is the first step of ribosome biogenesis, and cell growth is regulated during Pol I transcription initiation by the conserved factor Rrn3/TIF-IA in yeast/human. A wealth of structural information is available on Pol II and its general transcription factors (GTFs). Recently, also the architectures of Pol I and Pol III have been described by electron microscopy and the additional subunits that are specific to Pol I and Pol III have been identified as orthologs of the Pol II transcription factors TFIIF and TFIIE. Nevertheless, we still lack information about the architecture of the Pol I initiation complex and structural data is missing explaining the regulation of Pol I initiation mediated by its central transcription initiation factor Rrn3. The Rrn3 structure solved in this study reveals a unique HEAT repeat fold and indicates dimerization of Rrn3 in solution. However, the Rrn3-dimer is disrupted upon Pol I binding. The Rrn3 structure further displays a surface serine patch. Phosphorylation of this patch represses human Pol I transcription (Mayer et al, 2005; Mayer et al, 2004), and a phospho- mimetic patch mutation prevents Rrn3 binding to Pol I in vitro, and reduces S. cerevisiae cell growth and Pol I gene occupancy in vivo. This demonstrates a conserved regulation mechanism of the Pol I-Rrn3 interaction. Crosslinking indicates that Rrn3 does not only interact with Pol I subunits A43/14, but the interface further extends past the RNA exit tunnel and dock domain to AC40/19. The corresponding region of Pol II binds the Mediator head (Soutourina et al., 2011) that co-operates with TFIIB (Baek et al, 2006). Consistent with this, the Rrn3 binding partner, core factor subunit Rrn7, is predicted to be a TFIIB homologue. Taken together, our results provide the molecular basis of Rrn3-regulated Pol I initiation and cell growth and indicate a universally conserved architecture of eukaryotic transcription initiation complexes. 4 Publication Blattner C, Jennebach S, Herzog F, Mayer A, Cheung AC, Witte G, Lorenzen K, Hopfner K-P, Heck AJR, Aebersold R, Cramer P (2011). Molecular basis of Rrn3-regulated RNA polymerase I initiation and cell growth. Genes Dev 25(19): 2093-2105. Contributions The many experiments performed and results presented in this study were achieved with the help, advice and collaboration of several specialized researchers, whose contributions are listed below in detail. Claudia Blattner carried out all experiments apart from the ones listed below and determined the X-ray structure of Rrn3 with help and advice from Alan Cheung. SAXS analysis of the Rrn3 dimer was carried out by Gregor Witte. Native MS was carried out by Kristina Lorenzen. Protein crosslinking-MS analysis was carried out by Stefan Jennebach and Franz Herzog. ChIP analysis was done by Andreas Mayer. 5 Contents Erklärung..................................................................................................................................... 1 Ehrenwörtliche Versicherung ..................................................................................................... 1 Acknowledgements .................................................................................................................... 2 Summary ..................................................................................................................................... 4 Publication .................................................................................................................................. 5 Contributions .............................................................................................................................. 5 Contents ..................................................................................................................................... 6 1 Introduction ............................................................................................................................. 9 1.1 Eukaryotic Transcription Systems ................................................................................ 9 1.1.1 General Transcription Factors (GTFs) ...................................................................... 11 1.1.2 Structural studies on eukaryotic polymerase systems............................................ 12 1.2 rDNA transcription in the context of ribosome biogenesis and function .................. 14 1.2.1 Ribosome composition and biogenesis ................................................................... 14 1.2.2 rRNA production ...................................................................................................... 16 1.3 RNA Polymerase I transcription initiation complex ................................................... 17 1.3.1 Organization of the rRNA genes .............................................................................. 17 1.3.2 Initiation complex formation in mammals .............................................................. 17 1.3.3 Initiation complex formation in yeast ..................................................................... 18 1.4 Regulation of RNA Polymerase I transcription ..........................................................
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • AVILA-DISSERTATION.Pdf
    LOGOS EX MACHINA: A REASONED APPROACH TOWARD CANCER by Andrew Avila, B. S., M. S. A Dissertation In Biological Sciences Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Approved Lauren Gollahon Chairperson of the Committee Rich Strauss Sean Rice Boyd Butler Richard Watson Peggy Gordon Miller Dean of the Graduate School May, 2012 c 2012, Andrew Avila Texas Tech University, Andrew Avila, May 2012 ACKNOWLEDGEMENTS I wish to acknowledge the incredible support given to me by my major adviser, Dr. Lauren Gollahon. Without your guidance surely I would not have made it as far as I have. Furthermore, the intellectual exchange I have shared with my advisory committee these long years have propelled me to new heights of inquiry I had not dreamed of even in the most lucid of my imaginings. That their continual intellectual challenges have provoked and evoked a subtle sense of natural wisdom is an ode to their efficacy in guiding the aspirant to the well of knowledge. For this initiation into the mysteries of nature I cannot thank my advisory committee enough. I also wish to thank the Vice President of Research for the fellowship which sustained the initial couple years of my residency at Texas Tech. Furthermore, my appreciation of the support provided to me by the Biology Department, financial and otherwise, cannot be understated. Finally, I also wish to acknowledge the individuals working at the High Performance Computing Center, without your tireless support in maintaining the cluster I would have not have completed the sheer amount of research that I have.
    [Show full text]
  • Bidirectional Cooperation Between Ubtf1 and SL1 Determines RNA Polymerase I Promoter
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.07.447350; this version posted June 7, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Bidirectional cooperation between Ubtf1 and SL1 determines RNA Polymerase I promoter 2 recognition in cell and is negatively affected in the UBTF-E210K neuroregression syndrome. 3 4 Michel G. Tremblay1, Dany S. Sibai1,2, Melissa Valère1,2, Jean-Clément Mars1,2,+, Frédéric Lessard1, 5 Roderick T. Hori3, Mohammad M. Khan4, Victor Y. Stefanovsky1, Mark S. Ledoux5 and Tom Moss1,2*. 6 7 1Laboratory of Growth and Development, St-Patrick Research Group in Basic Oncology, Cancer 8 Division of the Quebec University Hospital Research Centre, Québec, Canada. 2Department of 9 Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, 10 Québec, Canada. 3Departments of Microbiology, Immunology and Biochemistry and 4Departments of 11 Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, 12 TN, USA. 5Department of Psychology, University of Memphis, Memphis TN and Veracity 13 Neuroscience LLC, Memphis, TN 14 15 +Present address, IRIC, Université de Montréal, Montréal, Québec, Canada 16 17 Correspondence should be addressed to; 18 Tom Moss, PhD, 19 Edifice St Patrick, 9 rue McMahon, Québec, QC, G1R 3S3, Canada. 20 E-mail. [email protected] 21 Tel. 1 418 691 5281 22 FAX 1 418 691 5439 23 24 Short title: Ubtf1-SL1 cooperation and the Ubtf-E210K syndrome.
    [Show full text]
  • Essential Genes and Their Role in Autism Spectrum Disorder
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Essential Genes And Their Role In Autism Spectrum Disorder Xiao Ji University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Bioinformatics Commons, and the Genetics Commons Recommended Citation Ji, Xiao, "Essential Genes And Their Role In Autism Spectrum Disorder" (2017). Publicly Accessible Penn Dissertations. 2369. https://repository.upenn.edu/edissertations/2369 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2369 For more information, please contact [email protected]. Essential Genes And Their Role In Autism Spectrum Disorder Abstract Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific oler in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality.
    [Show full text]
  • Table of Contents Table of Contents
    Table of contents Table of contents................................................................................................................. 1 Summary ............................................................................................................................. 3 Abbreviations ...................................................................................................................... 4 Gene Symbols I - Incidentals .............................................................................................. 5 Gene symbols II - Target Gene Names ............................................................................... 6 1. Introduction........................................................................................................... 12 1.1. The Pathos of the Crab ..................................................................................... 12 1.2. Cancer in the Molecular Age - a genetic and epigenetic disease..................... 13 1.3. Tumoral evolution............................................................................................. 14 1.4. DNA repair systems .......................................................................................... 17 1.4.1. DNA Mismatch Repair.............................................................................. 18 1.4.2. Double-strand Break Repair..................................................................... 19 1.4.3. Direct Repair...........................................................................................
    [Show full text]
  • Reorganization of the Host Epigenome by a Viral Oncogene
    Downloaded from genome.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Research Reorganization of the host epigenome by a viral oncogene Roberto Ferrari,1,2 Trent Su,1,3 Bing Li,1 Giancarlo Bonora,1,4 Amit Oberai,1 Yvonne Chan,1 Rajkumar Sasidharan,5 Arnold J. Berk,6,7 Matteo Pellegrini,2,5 and Siavash K. Kurdistani1,2,7,8,9 1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; 2Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA; 3Division of Oral Biology and Medicine, School of Dentistry, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; 4UCLA Bioinformatics Interdepartmental Degree Program, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA; 5Department of Molecular, Cellular, and Developmental Biology, University of California, Los Angeles, California 90095, USA; 6Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA; 7Molecular Biology Institute, University of California, Los Angeles, California 90095, USA; 8Department of Pathology and Laboratory of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA Adenovirus small e1a oncoprotein causes ~70% reduction in cellular levels of histone H3 lysine 18 acetylation (H3K18ac). It is unclear, however, where this dramatic reduction occurs genome-wide. ChIP-sequencing revealed that by 24 h after expression, e1a erases 95% of H3K18ac peaks in normal, contact-inhibited fibroblasts and replaces them with one-third as many at new genomic locations.
    [Show full text]
  • Assessment of Copy Number Variations in 120 Patients with Poland
    Vaccari et al. BMC Medical Genetics (2016) 17:89 DOI 10.1186/s12881-016-0351-x RESEARCHARTICLE Open Access Assessment of copy number variations in 120 patients with Poland syndrome Carlotta Maria Vaccari1, Elisa Tassano2, Michele Torre3, Stefania Gimelli4, Maria Teresa Divizia2, Maria Victoria Romanini5, Simone Bossi1, Ilaria Musante1, Maura Valle6, Filippo Senes7, Nunzio Catena7, Maria Francesca Bedeschi8, Anwar Baban2,10, Maria Grazia Calevo9, Massimo Acquaviva1, Margherita Lerone2, Roberto Ravazzolo1,2 and Aldamaria Puliti1,2* Abstract Background: Poland Syndrome (PS) is a rare congenital disorder presenting with agenesis/hypoplasia of the pectoralis major muscle variably associated with thoracic and/or upper limb anomalies. Most cases are sporadic, but familial recurrence, with different inheritance patterns, has been observed. The genetic etiology of PS remains unknown. Karyotyping and array-comparative genomic hybridization (CGH) analyses can identify genomic imbalances that can clarify the genetic etiology of congenital and neurodevelopmental disorders. We previously reported a chromosome 11 deletion in twin girls with pectoralis muscle hypoplasia and skeletal anomalies, and a chromosome six deletion in a patient presenting a complex phenotype that included pectoralis muscle hypoplasia. However, the contribution of genomic imbalances to PS remains largely unknown. Methods: To investigate the prevalence of chromosomal imbalances in PS, standard cytogenetic and array-CGH analyses were performed in 120 PS patients. Results: Following the application of stringent filter criteria, 14 rare copy number variations (CNVs) were identified in 14 PS patients in different regions outside known common copy number variations: seven genomic duplications and seven genomic deletions, enclosing the two previously reported PS associated chromosomal deletions. These CNVs ranged from 0.04 to 4.71 Mb in size.
    [Show full text]
  • Exposure to Childhood Abuse Is Associated with Human Sperm DNA Methylation Andrea L
    Roberts et al. Translational Psychiatry (2018) 8:194 DOI 10.1038/s41398-018-0252-1 Translational Psychiatry ARTICLE Open Access Exposure to childhood abuse is associated with human sperm DNA methylation Andrea L. Roberts 1, Nicole Gladish2,EvanGatev2,3, Meaghan J. Jones 2,YingChen4, Julia L. MacIsaac2, Shelley S. Tworoger4,5,S.BrynAustin6, Cigdem Tanrikut7, Jorge E. Chavarro4,5,8,AndreaA.Baccarelli9 and Michael S. Kobor 2,10 Abstract Offspring of persons exposed to childhood abuse are at higher risk of neurodevelopmental and physical health disparities across the life course. Animal experiments have indicated that paternal environmental stressors can affect sperm DNA methylation and gene expression in an offspring. Childhood abuse has been associated with epigenetic marks in human blood, saliva, and brain tissue, with statistically significant methylation differences ranging widely. However, no studies have examined the association of childhood abuse with DNA methylation in gametes. We examined the association of childhood abuse with DNA methylation in human sperm. Combined physical, emotional, and sexual abuse in childhood was characterized as none, medium, or high. DNA methylation was assayed in 46 sperm samples from 34 men in a longitudinal non-clinical cohort using HumanMethylation450 BeadChips. We performed principal component analysis and examined the correlation of principal components with abuse exposure. Childhood abuse was associated with a component that captured 6.2% of total variance in DNA methylation (p < 0.05). Next, we investigated the regions differentially methylated by abuse exposure. We identified 12 DNA regions differentially methylated by childhood abuse, containing 64 probes and including sites on genes associated with 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; neuronal function (MAPT, CLU), fat cell regulation (PRDM16), and immune function (SDK1).
    [Show full text]
  • Platform Abstracts
    American Society of Human Genetics 65th Annual Meeting October 6–10, 2015 Baltimore, MD PLATFORM ABSTRACTS Wednesday, October 7, 9:50-10:30am Abstract #’s Friday, October 9, 2:15-4:15 pm: Concurrent Platform Session D: 4. Featured Plenary Abstract Session I Hall F #1-#2 46. Hen’s Teeth? Rare Variants and Common Disease Ballroom I #195-#202 Wednesday, October 7, 2:30-4:30pm Concurrent Platform Session A: 47. The Zen of Gene and Variant 15. Update on Breast and Prostate Assessment Ballroom III #203-#210 Cancer Genetics Ballroom I #3-#10 48. New Genes and Mechanisms in 16. Switching on to Regulatory Variation Ballroom III #11-#18 Developmental Disorders and 17. Shedding Light into the Dark: From Intellectual Disabilities Room 307 #211-#218 Lung Disease to Autoimmune Disease Room 307 #19-#26 49. Statistical Genetics: Networks, 18. Addressing the Difficult Regions of Pathways, and Expression Room 309 #219-#226 the Genome Room 309 #27-#34 50. Going Platinum: Building a Better 19. Statistical Genetics: Complex Genome Room 316 #227-#234 Phenotypes, Complex Solutions Room 316 #35-#42 51. Cancer Genetic Mechanisms Room 318/321 #235-#242 20. Think Globally, Act Locally: Copy 52. Target Practice: Therapy for Genetic Hilton Hotel Number Variation Room 318/321 #43-#50 Diseases Ballroom 1 #243-#250 21. Recent Advances in the Genetic Basis 53. The Real World: Translating Hilton Hotel of Neuromuscular and Other Hilton Hotel Sequencing into the Clinic Ballroom 4 #251-#258 Neurodegenerative Phenotypes Ballroom 1 #51-#58 22. Neuropsychiatric Diseases of Hilton Hotel Friday, October 9, 4:30-6:30pm Concurrent Platform Session E: Childhood Ballroom 4 #59-#66 54.
    [Show full text]
  • Structural Mechanism of ATP-Independent Transcription
    RESEARCH ARTICLE Structural mechanism of ATP-independent transcription initiation by RNA polymerase I Yan Han1, Chunli Yan2,3‡, Thi Hoang Duong Nguyen4‡, Ashleigh J Jackobel5, Ivaylo Ivanov2,3, Bruce A Knutson5*, Yuan He1* 1Department of Molecular Biosciences, Northwestern University, Evanston, United States; 2Department of Chemistry, Georgia State University, Atlanta, United States; 3Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, United States; 4Howard Hughes Medical Institute, University of California, Berkeley, United States; 5Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States Abstract Transcription initiation by RNA Polymerase I (Pol I) depends on the Core Factor (CF) complex to recognize the upstream promoter and assemble into a Pre-Initiation Complex (PIC). Here, we solve a structure of Saccharomyces cerevisiae Pol I-CF-DNA to 3.8 A˚ resolution using single-particle cryo-electron microscopy. The structure reveals a bipartite architecture of Core Factor and its recognition of the promoter from À27 to À16. Core Factor’s intrinsic mobility correlates well with different conformational states of the Pol I cleft, in addition to the stabilization of either Rrn7 N-terminal domain near Pol I wall or the tandem winged helix domain of A49 at a partially overlapping location. Comparison of the three states in this study with the Pol II system *For correspondence: knutsonb@ suggests that a ratchet motion of the Core Factor-DNA sub-complex at upstream facilitates upstate.edu (BAK); yuanhe@ promoter melting in an ATP-independent manner, distinct from a DNA translocase actively northwestern.edu (YHe) threading the downstream DNA in the Pol II PIC.
    [Show full text]
  • 93G>A Promoter Polymorphism As A
    The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgementTown of the source. The thesis is to be used for private study or non- commercial research purposes only. Cape Published by the University ofof Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University ELUCIDATION OF THE OCCURRENCE OF EXTRACOLONIC CANCERS IN LYNCH SYNDROME Kusha Kalideen Town Supervisor: ProfessorCape R. Ramesar of Department of Clinical Laboratory Science Division of Human Genetics University Presented for M.Sc. (Med) In the School of Biomedical Sciences Faculty of Health Sciences University of Cape Town 2008 1 DECLARATION 1. I know that plagiarism is wrong. Plagiarism is to use another’s work and to pretend that it is ones own. 2. I have used the American Journal of Human Genetics convention for citation and referencing. Each significant contribution to, and quotation in, this essay/ report/ project/ from the work, or works, of other people has been attributed, and has cited and referenced. 3. This project is my own work using my Townown words. 4. I have not allowed, and will not allow, anyone to copy my work with the intention of passing if off as his or her own work. Cape of DATE.11 November 2008... STUDENT NAMEKUSHA KALIDEEN.. STUDENTUniversity NUMBER KLDKUS001. SIGNATURE. 2 Table of Contents Acknowledgments ............................................................................................... 7 List of abbrieviations ..........................................................................................
    [Show full text]
  • TIF-IA: an Oncogenic Target of Pre-Ribosomal RNA Synthesis Rui Jin, Emory University Wei Zhou, Emory University
    TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis Rui Jin, Emory University Wei Zhou, Emory University Journal Title: Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids Volume: Volume 1866, Number 2 Publisher: Elsevier: 12 months | 2016-12-01, Pages 189-196 Type of Work: Article | Post-print: After Peer Review Publisher DOI: 10.1016/j.bbcan.2016.09.003 Permanent URL: https://pid.emory.edu/ark:/25593/s6qwz Final published version: http://dx.doi.org/10.1016/j.bbcan.2016.09.003 Copyright information: © 2016 Elsevier B.V. All rights reserved. Accessed September 30, 2021 12:20 AM EDT HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Biochim Manuscript Author Biophys Acta. Manuscript Author Author manuscript; available in PMC 2017 December 01. Published in final edited form as: Biochim Biophys Acta. 2016 December ; 1866(2): 189–196. doi:10.1016/j.bbcan.2016.09.003. TIF-IA: an oncogenic target of pre-ribosomal RNA synthesis Rui Jin1 and Wei Zhou1,2,* 1Department of Hematology and Medical Oncology, The Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA 2Department of Pathology and Laboratory Medicine and Department of Human Genetics Emory University School of Medicine, Atlanta, GA, USA Abstract Cancer cells devote the majority of their energy consumption to ribosome biogenesis, and pre- ribosomal RNA transcription accounts for 30–50% of all transcriptional activity. This aberrantly elevated biological activity is an attractive target for cancer therapeutic intervention if approaches can be developed to circumvent the development of side effects in normal cells. TIF-IA is a transcription factor that connects RNA polymerase I with the UBF/SL-1 complex to initiate the transcription of pre-ribosomal RNA.
    [Show full text]