Objective The regulation of gene transcription governs eukaryotic cell growth and differentiation. Despite its importance, transcription regulation is not understood at a mechanistic level. Regulation occurs mainly during initiation, when the enzyme RNA polymerase II (Pol II) assembles with ~50 polypeptides on promoter DNA. Regulatory signals are transmitted by the 25-subunit Mediator, and convert the initiation complex into a productive elongation complex. Ten years after the solution of the Pol II structure (Cramer et al., Science 2000, 2001), elongation is understood, but the structure and regulatory control of the initiation complex remain largely unknown. Here I propose to solve this central problem of molecular genetics and obtain a movie that shows how a gene is activated. Our recent structure of Pol II with initiation factor TFIIB (Kostrewa et al. Nature 2009) provides the starting point for the proposed risky and challenging structure-function analysis of regulated initiation. First, we will determine structures of Pol II in the initiating state. Second, we will solve the structure of the essential, gene-regulatory 7-subunit head module of the Mediator core. Third, we will establish ¿nascent transcriptome analysis¿ as a novel technique that measures mRNA synthesis rates globally, and will use it to probe the mechanisms of regulated initiation by structure-based mutagenesis in vivo. Expected results will open new horizons for investigating the function of eukaryotic genomes, and will have a strong impact on biomedicine, since deregulated transcription underlies many diseases, including cancers and certain metabolic dysfunctions. This ground-breaking research requires the long-term, flexible commitment of the ERC, to successfully compete with teams in the US and Japan. Fields of science natural sciencesbiological sciencesmolecular biologymolecular geneticsnatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesgeneticsRNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological sciencesgeneticsgenomeseukaryotic genomes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS1 - ERC Advanced Grant - Molecular and Structural Biology and Biochemistry Call for proposal ERC-2010-AdG_20100317 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Coordinator MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Address Hofgartenstrasse 8 80539 Munchen Germany See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Administrative Contact Manfred Messerschmidt (Mr.) Principal investigator Patrick Cramer (Prof.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Germany EU contribution € 1 647 836,07 Address Hofgartenstrasse 8 80539 Munchen See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Administrative Contact Manfred Messerschmidt (Mr.) Principal investigator Patrick Cramer (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Other funding No data LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Participation ended Germany EU contribution € 578 230,93 Address Geschwister scholl platz 1 80539 Muenchen See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Higher or Secondary Education Establishments Administrative Contact Monika Bernhardt (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Other funding No data
