ChOReS · Chromatin re-organization in response to replication stress

Background and unmet need: The mammalian genome is a highly organized structure where distinctchromosomal domains occupy discrete territories and position in a non-random fashion. Genomeorganization also determines the proper functioning of various biological processes, including DNAreplication. Genome organization has been widely studied in the context of gene regulation, whilerecently the role of genome organization in mediating DNA damage repair at DSB sites has also cometo light. However, there is scarce information on how newly replicating region is organized in responseto replication stress.Hypothesis to be tested: My hypothesis is that stalled replication forks, especially at the regions proneto acquire breaks, undergo compartmentalization/re-organization within the 3-D nuclear space inresponse to replication stress to allow efficient fork protection and fork restart ability.Objectives: This unique multidisciplinary project will yield critical information to reveal hiddenconnections of chromatin organization, replication fork stability and chemoresistance. With this ERCproject, I will determine for the first time i) the mechanistic insights of chromatin organization changesmediated by chromatin remodeling activity in response to replication stress, ii) identify novel chromatinmobilizers associated with replication forks and iii) determine the significance of chromatin reorganizationto cope with replication stress for establishing resistance towards chemotherapeutic drugsin cancer cells and patient samples.Expected Outcomes: My project will not only advance our fundamental knowledge on spatial &temporal reorganization of chromatin architecture containing stressed replication forks, but it also has ahigh potential to contribute to identifying novel targets aimed at chromatin organizers that mediatesresistance towards replication stress inducing chemotherapeutics.