APC/C and SCFcyclin F Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry

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. [Display omitted] •SCFcyclin F and APC/CCdh1 constitute a reciprocal feedback circuit•Cyclin F is targeted for ubiquitylation and degradation by APC/CCdh1 in G1 phase•Cdh1 is targeted for ubiquitylation and degradation by SCFcyclin F in S-phase•Cyclin F contributes to Cdh1 degradation, APC/C inactivation, and S-phase entry Choudhury et al. report a temporally controlled, double-negative feedback loop between two cell-cycle E3 ubiquitin ligases, APC/C and SCFcyclin F. This direct feedback circuit controls APC/C inactivation at the G1/S boundary and cell-cycle progression and could represent a unique mechanistic feature of other oscillating systems.