Objective Replication-stress is a key driving force of cancer development, neurodegeneration and ageing. Many sources of replication stress associated with the initiation and elongation phases of DNA replication have been discovered. In contrast, little is known about the mechanisms of replication termination and termination-associated replication stress. Recent breakthroughs identified the first elements of a mechanism of replication termination that involved ubiquitination of the Mcm7 subunit of the CMG helicase. However, we do not know how terminating replisomes signal themselves for ubiquitination, nor how this is regulated both temporally and spatially along chromatin. By combining sophisticated single-molecule imaging techniques with the ability of Xenopus extracts to replicate DNA in a physiological manner, we will for the first time, be able to watch individual replication forks terminate. Importantly, our multidisciplinary and single-molecule approach will allow us to bypass the constraints posed by ensemble techniques that have hindered progress in this field. Specifically, we will define the spatial and temporal conditions upon which Mcm7 becomes ubiquitinated and how this is connected to the fate of the CMG helicase during termination. These observations will enable us to determine a complete mechanistic understanding of vertebrate replication termination for the first time. We will also discover how failed DNA replication termination triggers replication stress. Revealing these novel mechanisms of replication stress allows for new therapeutic targets to be identified and potentially facilitates new disease prevention strategies to be recognised. Fields of science natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncology Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2017 - Individual Fellowships Call for proposal H2020-MSCA-IF-2017 See other projects for this call Funding Scheme MSCA-IF-EF-RI - RI – Reintegration panel Coordinator THE UNIVERSITY OF BIRMINGHAM Net EU contribution € 183 454,80 Address Edgbaston B15 2TT Birmingham United Kingdom See on map Region West Midlands (England) West Midlands Birmingham Activity type Higher or Secondary Education Establishments 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 € 183 454,80
