FIGURE 5.

The change of state resulting from APC/C^CDH1 inactivation. Prior to this transition, the cell is in a state where proteolysis targeted by APC/C^CDH1 predominates, leading to the elimination of EMI1, its own inhibitor, together with substrate adaptors for the SCF-ubiquitin ligase, and components needed for DNA synthesis such as DBF4 and cyclin A. Factors required for replication origin licensing (CDC6 and CDT1) are stable whereas geminin – an inhibitor of CDT1 and hence licensing – is destroyed. Following the switch, SCF-mediated-proteolysis is promoted by the stabilization of its substrate adaptors (such as SKP2 and cyclin F). Origin firing becomes possible on accumulation of DBF4, acting together with CDK2 activity promoted first by cyclin E, then cyclin A, with activity further enhanced by p27 and/or p21 elimination. Origin relicensing is prevented in part by SCF-targeted degradation of the CDC6 and CDT1 licensing factors together with CDT1 suppression through geminin accumulation. Thus, at the point of APC^CDH1 inactivation, the cell passes from a state where origin licensing is possible but origin-firing is prevented, to one where origin-firing becomes possible but relicensing is suppressed. The change of state, once it occurs, is irreversible due to EMI1 stabilization and SCF-mediated elimination of CDH1.