Project description DEENESFRITPL Role of ATR kinase in nuclear mechanoadaptation In mammalian cells, the ataxia telangiectasia mutated and Rad3-related (ATR) kinase is part of the DNA damage response signalling pathway, involved in maintaining genome integrity by ensuring replication fork stability and coordinating cell cycle progression with DNA repair. ATR is a developmentally essential gene whose mutations have been linked to mental and growth retardation and microcephaly. Recent studies showed that ATR senses mechanical forces and translocates to the nuclear envelope (NE), suggesting an involvement in nuclear mechanoadaptation. The EU-funded MechanoATR project will use molecular biology techniques, imaging technology and the Xenopus laevis model to study the mechanism of ATR recruitment and activation at the NE as well as the physiological relevance of this translocation. Show the project objective Hide the project objective Objective ATR kinase is involved in maintaining genome integrity by ensuring replication fork stability and coordinating cell cycle progression with the DNA repair. ATR is a developmentally essential gene and in humans and hypomorphic mutations in ATR gene have been linked to Seckel syndrome characterized by mental and growth retardation and microcephaly. While the role of ATR in mediating DNA damage response has been extensively studied, the findings that it senses mechanical forces and translocates to the nuclear envelope (NE), coupled with preliminary data, suggest that this translocation is involved in nuclear mechanoadaptation. However, the mechanism of ATR recruitment and activation at the NE, proteins that are recruited or phosphorylated by ATR and the physiological relevance of ATR in a living organism, remain unknown. We will thus use multidisciplinary approach, advanced molecular biology techniques, cutting edge imaging modalities and the vertebrate model Xenopus Laevis in order to address these questions. Moreover, this proposal aims to identify the downstream consequences of this mechanical force-driven NE-ATR translocation, focusing on nuclear actin dynamics and epigenetic modification of histones. Fields of science natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesgeneticsgenomesnatural sciencesbiological sciencesmolecular biology Keywords nuclear envelope mechanotranduction nuclear actin ATR RASSF1A 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-2020 - Individual Fellowships Call for proposal H2020-MSCA-IF-2020 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator UNIVERSITY OF CYPRUS Net EU contribution € 145 941,12 Address AVENUE PANEPISTIMIOU 2109 AGLANTZI 1678 Nicosia Cyprus See on map Region Κύπρος Κύπρος Κύπρος 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 € 145 941,12
