Topoisomerase IIα represses transcription by enforcing promoter-proximal pausing
| Autor: | José Terrón-Bautista, Felipe Cortés-Ledesma, Gonzalo Millán-Zambrano, Andrés Herrero-Ruiz, Silvia Jimeno-González, Pedro Manuel Martínez-García, Jenna Ariel Lieberman |
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| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, European Research Council, Ministerio de Economía y Competitividad (España), Ministerio de Educación, Cultura y Deporte (España), Asociación Española Contra el Cáncer, [Herrero-Ruiz,A, Martínez-García,PM, Terrón-Bautista,J, Millán-Zambrano,G, Jimeno-González,S, Cortés-Ledesma,F] Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, Spain. [Lieberman,JA] Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD, USA. [Jimeno-González,S] Departamento de Genética, Universidad de Sevilla, Sevilla, Spain. [Herrero-Ruiz,A, Cortés-Ledesma,F] Topology and DNA Breaks Group, Spanish National Cancer Centre (CNIO), Madrid, Spain., This work was funded with grants from the Spanish and Andalusian governments (SAF2017-89619-R, CVI-7948, and European Regional Development Fund) and the European Research Council (ERC-CoG-2014-647359), and with individual fellowships for A.H.-R. (Contratos para la Formación de Doctores, BES-2015-071672, and Ministerio de Economía y Competitividad), S.J.-G. (Ramó n y Cajal, RYC-2015-17246, and Ministerio de Economía y Competitividad), J.T.-B. (Formación Profesorado Universitario, FPU15/03656, and Ministerio de Educación, Cultura y Deporte), and G.M.-Z. (AECC Postdoctoral Fellowships). CABIMER is supported by the Andalusian Government., Universidad de Sevilla. Departamento de Genética, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Protein Binding [Medical Subject Headings] Transcription Genetic Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings] RNA polymerase II Retinal Pigment Epithelium Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] chemistry.chemical_compound 0302 clinical medicine Transcription (biology) Gene expression Topoisomerase II Inhibitors DNA topoisomerases Biology (General) Poly-ADP-Ribose Binding Proteins Promoter Regions Genetic Cell Line Transformed Regulation of gene expression Elongación de la transcripción genética biology Chemistry DNA Superhelical Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds 1-Ring::Pyrimidines::Pyrimidinones::Barbiturates::Thiobarbiturates [Medical Subject Headings] Thiobarbiturates DNA supercoiling Cell biology DNA topology Anatomy::Cells::Cells Cultured::Cell Line::Cell Line Transformed [Medical Subject Headings] Chemicals and Drugs::Nucleic Acids Nucleotides and Nucleosides::Nucleic Acids::DNA::DNA Circular::DNA Superhelical [Medical Subject Headings] DNA supercoil RNA Polymerase II Proto-Oncogene Proteins c-fos Anatomy::Sense Organs::Eye::Retina::Retinal Pigment Epithelium [Medical Subject Headings] Protein Binding QH301-705.5 Article General Biochemistry Genetics and Molecular Biology promoter-proximal pausing 03 medical and health sciences Humans transcription elongation Genes Immediate-Early Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes Immediate-Early [Medical Subject Headings] Topoisomerase Promoter Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::RNA Nucleotidyltransferases::DNA-Directed RNA Polymerases::RNA Polymerase II [Medical Subject Headings] Epithelial Cells Anatomy::Cells::Epithelial Cells [Medical Subject Headings] 030104 developmental biology Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Topoisomerase Inhibitors::Topoisomerase II Inhibitors [Medical Subject Headings] DNA Topoisomerases Type II ADN-topoisomerasas Gene Expression Regulation biology.protein gene expression Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Isomerases::DNA Topoisomerases::DNA Topoisomerases Type II [Medical Subject Headings] 030217 neurology & neurosurgery DNA Expresión génica Chemicals and Drugs::Amino Acids Peptides and Proteins::Proteins::Nuclear Proteins::Proto-Oncogene Proteins c-fos [Medical Subject Headings] |
| Zdroj: | Cell Reports, Vol 35, Iss 2, Pp 108977-(2021) Digital.CSIC. Repositorio Institucional del CSIC instname idUS. Depósito de Investigación de la Universidad de Sevilla Fundacion Sancho el Sabio Fundazioa (FSS) Cell Reports |
| ISSN: | 2211-1247 |
| Popis: | Summary Accumulation of topological stress in the form of DNA supercoiling is inherent to the advance of RNA polymerase II (Pol II) and needs to be resolved by DNA topoisomerases to sustain productive transcriptional elongation. Topoisomerases are therefore considered positive facilitators of transcription. Here, we show that, in contrast to this general assumption, human topoisomerase IIα (TOP2A) activity at promoters represses transcription of immediate early genes such as c-FOS, maintaining them under basal repressed conditions. Thus, TOP2A inhibition creates a particular topological context that results in rapid release from promoter-proximal pausing and transcriptional upregulation, which mimics the typical bursting behavior of these genes in response to physiological stimulus. We therefore describe the control of promoter-proximal pausing by TOP2A as a layer for the regulation of gene expression, which can act as a molecular switch to rapidly activate transcription, possibly by regulating the accumulation of DNA supercoiling at promoter regions. Graphical abstract Highlights • Catalytic inhibition of TOP2A results in a global reduction in promoter-proximal pausing • Catalytic inhibition of TOP2A upregulates transcription of immediate early genes (IEGs) • IEG upregulation occurs independently of DNA breaks or cellular stress • IEG upregulation depends on the accumulation of negative supercoiling at promoter regions Herrero-Ruiz et al. analyze the function of DNA topoisomerase II in transcriptional regulation. The results reveal that TOP2A activity favors promoter-proximal pausing of RNA polymerase II and repression of immediate early genes in a mechanism that is independent of DNA break formation and involves the control of DNA supercoiling at promoters. |
| Databáze: | OpenAIRE |
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