title: Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control.
abstract: Cells respond to DNA damage by activating cell cycle checkpoints to delay proliferation and facilitate DNA repair. Here, to uncover new checkpoint regulators, we perform RNA interference screening targeting genes involved in ubiquitylation processes. We show that the F-box protein cyclin F plays an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein cyclin F with suppression of the B-Myb/cyclin A pathway to ensure a DNA damage-induced checkpoint response in G2.
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Ditte Kjærsgaard
authors.initials: DK
authors.lastname: Klein
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Saskia
authors.initials: S
authors.lastname: Hoffmann
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Ahlskog
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: O'Hanlon
authors.affiliation: Department of Molecular Oncology, Medical School, University of Leipzig, Semmelweisstr. 14, 04103, Leipzig, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Quaas
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Larsen
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Rolland
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Heike I
authors.initials: HI
authors.lastname: Rösner
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: David
authors.initials: D
authors.lastname: Walter
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Arne Nedergaard
authors.initials: AN
authors.lastname: Kousholt
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Tobias
authors.initials: T
authors.lastname: Menzel
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Lees
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Jens Vilstrup
authors.initials: JV
authors.lastname: Johansen
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Kings Buildings, Mayfield Road, Edinburgh EH9 3JR, Scotland.
authors.forename: Juri
authors.initials: J
authors.lastname: Rappsilber
authors.affiliation: Department of Molecular Oncology, Medical School, University of Leipzig, Semmelweisstr. 14, 04103, Leipzig, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Engeland
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Claus Storgaard
authors.initials: CS
authors.lastname: Sørensen
mesh_terms: D059447:Cell Cycle Checkpoints / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D016213:Cyclins / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008156:Luciferases; D016297:Mutagenesis, Site-Directed; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C503669:CCNF protein, human; D018797:Cell Cycle Proteins; D016213:Cyclins; D017931:DNA Primers; C064352:MYBL2 protein, human; D034741:RNA, Small Interfering; D015534:Trans-Activators; D008156:Luciferases