Project description DEENESFRITPL Dissecting the mechanism of centromere formation During cell division, faithful parental DNA segregation is ensured through the binding of chromosomes to microtubules, part of the cell cytoskeleton. Specialised protein complexes known as kinetochores are central to this binding which takes place at the centromeres of chromosomes. Accumulating evidence indicates that the formation of centromeres is mediated by epigenetic mechanisms involving the histone variant CENP-A. Funded by the European Research Council, the RECEPIANCE project aims to understand the molecular mechanism of CENP-A deposition and how it is regulated by recreating this process in vitro using recombinant proteins. The work will provide fundamental insight into the mechanism of DNA segregation in health and disease. Show the project objective Hide the project objective Objective Accurate segregation of the parental genome to the daughter cells during mitosis is essential for cell and organismal viability, protecting against cell death or cellular transformation. Kinetochores are crucial for accurate chromosome segregation because they link chromosomes to spindle microtubules. Kinetochores sprout from unique chromosomal loci named centromeres. In most eukaryotes, centromere specification does not rely on defined DNA sequences. Rather, centromere specification relies on epigenetic mechanisms, the most prominent of which is identified in the enrichment at centromeres of the histone H3 variant CENP-A. Deposition of new CENP-A at every cell cycle is vital for centromere maintenance through cell division. RECEPIANCE aims to dissect the molecular mechanism of CENP-A deposition through reductionist approach based on two main pillars, biochemical reconstitution and structural analysis. The CENP-A deposition machinery consists of chromatin-remodelling factors, histone chaperones, and accessory factors, including the Mis18 complex, HJURP, RbAb46/48, the FACT complex, RSF, CHD1, and additional currently less characterized proteins. The CENP-A deposition machinery is recruited to centromeres in a cell cycle-regulated manner by inner kinetochore proteins associated with CENP-A, most notably CENP-C. The hypothesis inspiring this proposal is that the CENP-A deposition machinery operates on a unit containing at least one CENP-A nucleosome and a neighboring canonical H3 nucleosome, with the latter being the target for exchange with new CENP-A. Our ability to reconstitute the centromere-inner kinetochore interface puts us in an ideal position to study how the CENP-A deposition machinery is recruited to centromeres in vitro, dissecting the crucial binding interfaces and studying them biochemically and structurally. The ultimate goal of RECEPIANCE is to reconstitute the ATP-dependent exchange of H3 with CENP-A in vitro exclusively with recombinant proteins. Fields of science natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticschromosomesnatural sciencesbiological sciencesgeneticsgenomes Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-ADG-2014 - ERC Advanced Grant Call for proposal ERC-2014-ADG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Host institution MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Net EU contribution € 2 064 583,00 Address HOFGARTENSTRASSE 8 80539 Munchen Germany See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 064 583,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Germany Net EU contribution € 2 064 583,00 Address HOFGARTENSTRASSE 8 80539 Munchen See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 064 583,00
