Objectif Chromatin structure is influenced by covalent modifications of histones which lead to the recruitment of proteins that recognize specific regions in the genome. Histones undergo a variety of post-translational modifications. These modifications modulate a multitude of DNA based processes such as transcription, repair, replication and chromatin dynamics. Methylation is one of these important modifications. In this proposal the histone methyltransferase Dot1 (disruptor of telomeric silencing) is investigated. Dot1 methylates lysine 79 located in the globular histone-fold of histone H3 and is therefore the first histone modification enzyme discovered that modifies a residue in the core region and not in the N-terminal part. This methylation requires minimally a nucleosome core particle (NCP), consisting of 147bp of DNA and a histone octamer containing a central H3-H4 tetramer and two H2A-H2B dimers. The ability of Dot1 to bind and modify a nucleosomal substrate makes it an ideal model enzyme to study the interaction of the nucleosome with such regulatory factors. In this approach x-ray crystallography combined with disulphide crosslinking will be used to study the Dot1/NCP interaction. Heterochromatic gene silencing, DNA repair, embryonic development and human leukemia are only some of the processes Dot1 is involved in and they also contribute greatly to its interest. As part of leukemia pathogenesis Dot1 was shown to interact with the MLL (mixed lineage leukemia) fusion protein AF10, Dot1 therefore plays a significant role in misregulation of MLL oncogenes. The structural information obtained by x-ray crystallography about the Dot1/AF10 interaction will give insights into leukemia pathogenesis whereas structural studies of the Dot1/chromatin interaction would be a major step to understand the interaction between chromatin and chromatin associated factors and would therefore be a milestone in chromatin biology. Champ scientifique natural sciencesbiological sciencesgeneticsDNAnatural sciencesearth and related environmental sciencesgeologymineralogycrystallographynatural sciencesbiological sciencesdevelopmental biologymedical and health sciencesclinical medicineoncologyleukemianatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Appel à propositions FP7-PEOPLE-2012-IEF Voir d’autres projets de cet appel Régime de financement MC-IEF - Intra-European Fellowships (IEF) Coordinateur EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH Contribution de l’UE € 184 709,40 Adresse Raemistrasse 101 8092 Zuerich Suisse Voir sur la carte Région Schweiz/Suisse/Svizzera Zürich Zürich Type d’activité Higher or Secondary Education Establishments Contact administratif Rudi Glockshuber (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
