Objective Nuclear actin-related proteins (ARPs) are stoichiometric subunits of chromatin remodelers and specifically recognize and bind to (modified) histone proteins. In the case of the chromatin modifiers INO80, SWR1 and NuA4, canonical monomeric actin is also an important constituent of these large macromolecular complexes and actively takes part in the remodeling reaction. The main characteristic of actin, however, is its dynamic nature and its capacity to form polymeric actin filaments, which is tightly regulated by a plethora of actin binding proteins amongst them also nuclear ARPs. Interestingly, alteration of actin levels strongly sensitize cells to DNA damage in an enigmatic process and the chromatin-binding nuclear ARPs are obviously strong candidates that possibly couple actin homeostasis in the nucleus with a putative role in genomic integrity. Missing from the field is a genetic approach to specifically mutate actin in the chromatin modifier context and to analyse the impact of polymerization mutants in genomic integrity. The central hypothesis in this research proposal is that nuclear ARP/chromatin remodeler associated actin is a key mediator in genomic maintenance. This assumption is based on the very recent finding in the Gasser laboratory that interference with actin homeostasis renders cells to be hypersensitive to genomic insult as chromosomes are rapidly fragmented in presence of actin depolymerizing agent Latrunculin A and DNA damaging agent zeocin. The major challenge in this project is to bypass the paramount role of actin in the cytoskeleton and to focus on the fraction of nuclear ARP associated actin.This will be achieved by genetically replacing nuclear ARPs with ARP-actin fusion constructs in the budding yeast S. cerevisiae, which will allow me to introduce actin mutants exclusively in a chromatin modifying context. Concomitantly, a new approach to generate actin probes for microscopy based on bicyclic peptides will be applied. Fields of science natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesphysical sciencesopticsmicroscopynatural sciencesbiological sciencesgeneticschromosomesmedical and health sciencesbasic medicinephysiologyhomeostasis 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) Topic(s) FP7-PEOPLE-2013-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Call for proposal FP7-PEOPLE-2013-IEF See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION EU contribution € 207 928,80 Address Maulbeerstrasse 66 4058 Basel Switzerland See on map Region Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt Activity type Research Organisations Administrative Contact Dorothy Searles (Mrs.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data