Herrero-Ruiz, AndrésMartínez-García, Pedro ManuelTerrón-Bautista, JoséMillán-Zambrano, GonzaloLieberman, Jenna ArielJimeno-González, SilviaCortes-Ledesma, Felipe2024-10-282024-10-282021-04-13Cell Rep . 2021 Apr 13;35(2):108977https://hdl.handle.net/20.500.12105/25319We thank the Genomics Core facilities at CABIMER and the EMBL (GeneCore) for the generation of the high-thoughput sequencing data and O. Fernandez-Capetillo for comments. Computational analyses were run on the High Perfomance Computing cluster provided by the Centro Informatico Cientifico de Andalucia (CICA). 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 Formacion de Doctores, BES-2015-071672, and Ministerio de Economia y Competitividad); S.J.-G. (Ramon y Cajal, RYC-2015-17246, and Ministerio de Economia y Competitividad); J.T.-B. (Formacion Profesorado Universitario, FPU15/03656, and Ministerio de Educacion, Cultura y Deporte); and G.M.-Z. (AECC Postdoctoral Fellowships). CABIMER is supported by the Andalusian Government.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.engVoRhttp://creativecommons.org/licenses/by/4.0/DNA supercoilingDNA topoisomerasesDNA topologygene expressionpromoter-proximal pausingtranscription elongationAttribution 4.0 International33852840352108977Cell Repopen access