Objetivo The regulation of gene transcription by RNA polymerase (Pol) II underlies cell differentiation and organism development, and its dysregulation causes many cancers. Transcription regulation occurs during initiation, when Pol II assembles with initiation factors on promoter DNA, but also during mRNA chain elongation, when Pol II pauses near the promoter before it restarts upon activation. Our previous ERC Advanced Grant ‘TRANSIT’ enabled us to provide molecular insights into yeast Pol II initiation and its regulation by the Mediator coactivator complex (Plaschka et al., Nature 2015; Sainsbury et al., Nature 2012, Lariviere et al, Nature 2012). Here, with our new proposal ‘TRANSREGULON’ we wish to open a new frontier and provide the structural basis for mammalian Pol II regulation during elongation. We will use an integrated structural biology approach combining X-ray crystallography, cryo-electron microscopy, and crosslinking, to obtain the first atomic structure of a mammalian Pol II enzyme (aim 1), the structure of the negative elongation factor NELF (aim 2), which is required for promoter-proximal pausing by mammalian Pol II, and the threedimensional architecture of the promoter-proximally paused Pol II complex (aim 3) containing the multiprotein pausing factors NELF and DSIF, and eventually also the pause release factor p-TEFb. This ground-breaking work will make the transition from yeast to human structural biology of transcription, will provide the molecular basis for a central mechanism of cellular regulation, and will advance structural biology methods for dissecting large and transient mammalian multicomponent complexes. Ámbito científico natural sciencesbiological sciencesgeneticsDNAnatural sciencesearth and related environmental sciencesgeologymineralogycrystallographynatural sciencesbiological sciencesgeneticsRNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological sciencesmolecular biologystructural biology Programa(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Tema(s) ERC-ADG-2015 - ERC Advanced Grant Convocatoria de propuestas ERC-2015-AdG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-ADG - Advanced Grant Institución de acogida MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Aportación neta de la UEn € 2 496 250,00 Dirección HOFGARTENSTRASSE 8 80539 Munchen Alemania Ver en el mapa Región Bayern Oberbayern München, Kreisfreie Stadt Tipo de actividad Research Organisations Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 2 496 250,00 Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación neta de la UE Ampliar todo Contraer todo MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Alemania Aportación neta de la UEn € 2 496 250,00 Dirección HOFGARTENSTRASSE 8 80539 Munchen Ver en el mapa Región Bayern Oberbayern München, Kreisfreie Stadt Tipo de actividad Research Organisations Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 2 496 250,00