title: SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication.
abstract: Maintenance of genome stability requires that DNA is replicated precisely once per cell cycle. This is believed to be achieved by limiting replication origin licensing and thereby restricting the firing of each replication origin to once per cell cycle. CDC6 is essential for eukaryotic replication origin licensing, however, it is poorly understood how CDC6 activity is constrained in higher eukaryotes. Here we report that the SCF(Cyclin F) ubiquitin ligase complex prevents DNA re-replication by targeting CDC6 for proteasomal degradation late in the cell cycle. We show that CDC6 and Cyclin F interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. Absence of Cyclin F or expression of a stable mutant of CDC6 promotes re-replication and genome instability in cells lacking the CDT1 inhibitor Geminin. Together, our work reveals a novel SCF(Cyclin F)-mediated mechanism required for precise once per cell cycle replication.
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N 2200, Denmark.
authors.forename: David
authors.identifier: http://orcid.org/0000-0003-4363-0339
authors.initials: D
authors.lastname: Walter
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N 2200, Denmark.
authors.forename: Saskia
authors.initials: S
authors.lastname: Hoffmann
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Athens GR-11527, Greece.
authors.forename: Eirini-Stavroula
authors.initials: ES
authors.lastname: Komseli
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Kings Buildings, Max Born Crescent, Edinburgh EH9 3BF, Scotland.|Department of Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin 13355, Germany.
authors.forename: Juri
authors.identifier: http://orcid.org/0000-0001-5999-1310
authors.initials: J
authors.lastname: Rappsilber
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Athens GR-11527, Greece.|Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N 2200, Denmark.
authors.forename: Claus Storgaard
authors.initials: CS
authors.lastname: Sørensen
mesh_terms: D020816:Amino Acid Motifs; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C503669:CCNF protein, human; C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D016213:Cyclins; D009687:Nuclear Proteins; D044843:SKP Cullin F-Box Protein Ligases
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