β-TrCP- and Casein Kinase II-Mediated Degradation of Cyclin F Controls Timely Mitotic Progression
Ioanna Mavrommati,
Roberta Faedda,
Giovanni Galasso,
Jie Li,
Kamila Burdova,
Roman Fischer,
Benedikt M. Kessler,
Zunamys I. Carrero,
Daniele Guardavaccaro,
Michele Pagano,
Vincenzo D’Angiolella
Affiliations
Ioanna Mavrommati
Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
Roberta Faedda
Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
Giovanni Galasso
Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
Jie Li
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA
Kamila Burdova
Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
Roman Fischer
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK
Benedikt M. Kessler
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK
Zunamys I. Carrero
Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
Daniele Guardavaccaro
Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands; Department of Biotechnology, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy
Michele Pagano
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA; Corresponding author
Vincenzo D’Angiolella
Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Corresponding author
Summary: Orderly progressions of events in the cell division cycle are necessary to ensure the replication of DNA and cell division. Checkpoint systems allow the accurate execution of each cell-cycle phase. The precise regulation of the levels of cyclin proteins is fundamental to coordinate cell division with checkpoints, avoiding genome instability. Cyclin F has important functions in regulating the cell cycle during the G2 checkpoint; however, the mechanisms underlying the regulation of cyclin F are poorly understood. Here, we observe that cyclin F is regulated by proteolysis through β-TrCP. β-TrCP recognizes cyclin F through a non-canonical degron site (TSGXXS) after its phosphorylation by casein kinase II. The degradation of cyclin F mediated by β-TrCP occurs at the G2/M transition. This event is required to promote mitotic progression and favors the activation of a transcriptional program required for mitosis. : Mavrommati et al. identify how cyclin F is regulated during mitosis by proteolysis. Cyclin F is ubiquitylated by β-TrCP after phosphorylation by CKII on S704 within a TSGXXS degron. β-TrCP-mediated degradation of cyclin F favors timely mitotic progression through the control of a B-Myb transcriptional program. Keywords: F-box protein, cyclin F, β-TrCP, mitosis, cell cycle, ubiquitin, SCF, CRLs, CKII
