APC/C and SCFcyclin F Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry
Rajarshi Choudhury,
Thomas Bonacci,
Anthony Arceci,
Debojyoti Lahiri,
Christine A. Mills,
Jennifer L. Kernan,
Timothy B. Branigan,
James A. DeCaprio,
Daniel J. Burke,
Michael J. Emanuele
Affiliations
Rajarshi Choudhury
Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Thomas Bonacci
Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Anthony Arceci
Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Debojyoti Lahiri
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA
Christine A. Mills
Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Jennifer L. Kernan
Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Timothy B. Branigan
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
James A. DeCaprio
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Daniel J. Burke
Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA
Michael J. Emanuele
Lineberger Comprehensive Cancer Center and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
The anaphase promoting complex/cyclosome (APC/C) is an ubiquitin ligase and core component of the cell-cycle oscillator. During G1 phase, APC/C binds to its substrate receptor Cdh1 and APC/CCdh1 plays an important role in restricting S-phase entry and maintaining genome integrity. We describe a reciprocal feedback circuit between APC/C and a second ubiquitin ligase, the SCF (Skp1-Cul1-F box). We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCFcyclin F. Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. These data indicate that the coordinated, temporal ordering of cyclin F and Cdh1 degradation, organized in a double-negative feedback loop, represents a fundamental aspect of cell-cycle control. This mutual antagonism could be a feature of other oscillating systems.
