Objective Accurate chromosomal DNA replication is of fundamental importance for cellular function, genome integrity and development. In response to replication perturbations, DNA damage response (DDR) and DNA damage tolerance (DDT) pathways become activated and are crucial for detection and tolerance of lesions, as well as for facilitating replication completion and supporting chromosome structural integrity. While important functions and key players of these regulatory processes have been outlined, much less is known about the choreography and mechanistic interplay between DDR and DDT during replication. Moreover, the principles by which they uniquely or commonly affect replication-associated chromosome integrity remain poorly understood.Here, we will use novel tools and a palette of ingenious genetic, molecular and proteomic based experimental strategies, to investigate the replication stress response triggered by diverse endogenous and exogenous cues, and to identify the underlying mechanisms. We will define the principles of local and temporal regulation of DDT in response to genotoxic stress, with a focus on the mechanisms of SUMO-regulated DNA metabolism processes. Additionally, we will investigate the topological DNA transitions triggered at intrinsically difficult to replicate genomic regions, stalled and terminal forks, with the aim of identifying key mechanisms and regulators of replication integrity at specific complex genomic regions or following specific types of replication stress. Finally, we will explore the relationship between DDT, replication fork architecture and sister chromatid cohesion in the context of DDR- and SUMO-orchestrated DNA transactions. We expect that these studies will reveal new aspects of how replication-associated DNA metabolism processes are inter-related and regulated, uniformly or at specific loci in the genome, and will break new ground in areas of replication mechanisms and chromosome integrity in general. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticschromosomesnatural sciencesbiological sciencesgeneticsgenomes Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-CoG-2015 - ERC Consolidator Grant Call for proposal ERC-2015-CoG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution IFOM-ISTITUTO FONDAZIONE DI ONCOLOGIA MOLECOLARE ETS Net EU contribution € 1 991 250,00 Address VIA ADAMELLO 16 20139 Milano Italy See on map Region Nord-Ovest Lombardia Milano 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 € 1 991 250,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all IFOM-ISTITUTO FONDAZIONE DI ONCOLOGIA MOLECOLARE ETS Italy Net EU contribution € 1 991 250,00 Address VIA ADAMELLO 16 20139 Milano See on map Region Nord-Ovest Lombardia Milano 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 € 1 991 250,00