Journal
CELL REPORTS
Volume 16, Issue 12, Pages 3359-3372Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.08.058
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Funding
- Cancer Center Core Support Grant [P30 CA016086]
- University Cancer Research Fund
- Susan G. Komen Foundation [CCR14298820]
- Jimmy-V Foundation
- US Public Health Service [R01GM120309, R01CA63113, R01CA173023]
- North Carolina State University
- F31 training grant [CA189328]
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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/C-Cdh1 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.
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