Herrero-Ruiz, AndrésMartínez-García, Pedro ManuelTerrón-Bautista, JoséMillán-Zambrano, GonzaloLieberman, Jenna ArielJimeno-González, SilviaCortés-Ledesma, Felipe2022-05-202022-05-202021-04-13Herrero-Ruiz A, Martínez-García PM, Terrón-Bautista J, Millán-Zambrano G, Lieberman JA, Jimeno-González S, et al. Topoisomerase IIα represses transcription by enforcing promoter-proximal pausing. Cell Rep. 2021 Apr 13;35(2):108977http://hdl.handle.net/10668/3655Accumulation 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.enAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/DNA supercoilingDNA topoisomerasesDNA topologyGene expressionPromoter-proximal pausingTranscription elongationADN-topoisomerasasExpresión génicaElongación de la transcripción genéticaMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, TransformedMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Isomerases::DNA Topoisomerases::DNA Topoisomerases, Type IIMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::DNA::DNA, Circular::DNA, SuperhelicalMedical Subject Headings::Anatomy::Cells::Epithelial CellsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression RegulationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Immediate-EarlyMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Protein BindingMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear Proteins::Proto-Oncogene Proteins c-fosMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::RNA Nucleotidyltransferases::DNA-Directed RNA Polymerases::RNA Polymerase IIMedical Subject Headings::Anatomy::Sense Organs::Eye::Retina::Retinal Pigment EpitheliumMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Barbiturates::ThiobarbituratesMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Topoisomerase Inhibitors::Topoisomerase II Inhibitorsresearch article33852840Acceso abierto10.1016/j.celrep.2021.1089772211-1247PMC8052185