Obiettivo In each cell cycle, eukaryotic cells must faithfully replicate large genomes in a relatively short time. This is accomplished by initiating DNA replication from many replication origins distributed along chromosomes. Ensuring that each origin is efficiently activated once and only once per cell cycle is crucial for maintaining the integrity of the genome. Recent evidence indicates that defects in the regulation of origin firing may be important contributors to genome instability in cancer. Strict once per cell cycle DNA replication is achieved by a two-step mechanism. DNA replication origins are first licensed by loading an inactive DNA helicase (Mcm2-7) into pre-replicative complexes (pre-RCs). This can only occur during G1 phase. Initiation then occurs during S phase, triggered by cyclin dependent kinases (CDKs) and Dbf4-dependent kinase (DDK), which promote recruitment of proteins required for helicase activation and replisome assembly. Research proposed herein will lead to a deeper understanding of the mechanism and regulation of DNA replication. We have reconstituted the licensing reaction with purified proteins which will be used to characterise the mechanism of licensing and the mechanism by which licensing is regulated in the cell cycle. We will also use this system to reconstitute events leading to the initiation of DNA replication. We will use genetic and biochemical approaches to characterise the mechanisms by which perturbed licensing causes gross chromosome rearrangements. We will also explore mechanisms involved in regulating the temporal programme of origin firing and how origin firing is regulated in response to DNA damage. Work in budding yeast and mammalian cells will be pursued in parallel to exploit the specific advantages of each system. Campo scientifico natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticschromosomesnatural sciencesbiological sciencesgeneticsgenomes Programma(i) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) ERC-AG-LS1 - ERC Advanced Grant - Molecular and Structural Biology and Biochemistry Invito a presentare proposte ERC-2009-AdG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-AG - ERC Advanced Grant Istituzione ospitante THE FRANCIS CRICK INSTITUTE LIMITED Contributo UE € 2 449 998,99 Indirizzo 1 MIDLAND ROAD NW1 1AT London Regno Unito Mostra sulla mappa Regione London Inner London — West Camden and City of London Tipo di attività Research Organisations Ricercatore principale John Diffley (Dr.) Contatto amministrativo Heather Joanne Woods (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Beneficiari (2) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto THE FRANCIS CRICK INSTITUTE LIMITED Regno Unito Contributo UE € 2 449 998,99 Indirizzo 1 MIDLAND ROAD NW1 1AT London Mostra sulla mappa Regione London Inner London — West Camden and City of London Tipo di attività Research Organisations Ricercatore principale John Diffley (Dr.) Contatto amministrativo Heather Joanne Woods (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato CANCER RESEARCH UK LBG Partecipazione conclusa Regno Unito Contributo UE Nessun dato Indirizzo 2 Redman Place E20 1JQ LONDON Mostra sulla mappa Regione London Inner London — West Camden and City of London Tipo di attività Research Organisations Contatto amministrativo Holly Elphinstone (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
