Objectif The objective of this proposal is to define the molecular basis behind the origin and protection of unstable repetitive DNA sequences during sexual reproduction. Eukaryotic genomes contain large amounts of repetitive elements that serve vital roles in cellular physiology. However, repetitive elements are intrinsically unstable, which is caused by a high likelihood for incorrect repair when DNA breaks form within repetitive elements. During sexual reproduction, numerous DNA breaks are actively introduced into the genome, and repetitive sequences particularly threaten genome stability during this specialized developmental program. We will use the repetitive budding yeast ribosomal (r)DNA array as a model locus to study repetitive DNA instability. Our previous work showed that the outermost elements of this large repetitive array (i.e. rDNA array boundaries) are DNA break ‘fragile sites’, which attract DNA breaks during sexual reproduction. Importantly, we isolated the first known enzymatic ‘anti-DNA break’ system, which minimizes DNA break formation at rDNA array boundaries and as such is crucially required to maintain genome stability.In the experiments outlined here, we will use a combination of genomics, molecular biology and biochemistry to: 1) Interrogate the origins of the vulnerability of the repetitive rDNA boundaries for DNA breaks, and2) Define how a first-in-class ‘anti-DNA break’ system locally protects against DNA break formation. These studies will serve as a paradigm for repetitive DNA instability, yielding major insights into the general principles that govern protection of vulnerable genomic elements during sexual reproduction. It is well established that incorrect repair of DNA breaks involving repetitive sequences during sexual reproduction causes a myriad of human congenital disorders. Therefore, we foresee that insights gained from this work have the potential to help us understand the aetiology of human genetic disease. Champ scientifique natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesgeneticshereditynatural sciencesbiological sciencesgeneticschromosomesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological sciencesgeneticsgenomeseukaryotic genomes Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-StG-2014 - ERC Starting Grant Appel à propositions ERC-2014-STG Voir d’autres projets de cet appel Régime de financement ERC-STG - Starting Grant Institution d’accueil MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Contribution nette de l'UE € 1 500 000,00 Adresse HOFGARTENSTRASSE 8 80539 Munchen Allemagne Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Research Organisations Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 1 500 000,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Allemagne Contribution nette de l'UE € 1 500 000,00 Adresse HOFGARTENSTRASSE 8 80539 Munchen Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Research Organisations Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 1 500 000,00