Figure 1. Cell cycle machinery and checkpoints.

The proceeding of the cell cycle depends on subsequential degradation of Cyclins and other key cell cycle regulators by the APC/C and SCF E3 ligase complexes, to ensure the faithful completion of DNA replication and orderly cell division. In G1 phase, Cyclin D-CDK4/6 and Cyclin E-CDK2 phosphorylate Rb protein, leading to the relief from G1/S checkpoint by triggering E2F release from Rb and the repressive complex for the transcription of downstream targets, to prepare for the synthesis of protein and DNA. After the replication of genome DNA in S phase, cells in G2 phase pass through the G2/M checkpoint, where errors during DNA synthesis activate the DNA damage pathway to repress Cyclin B-CDK1 kinase activity through the ATR-Chk1-WEE1/CDC25C signaling axis. During mitosis, the spindle assembly checkpoint is governed by MCC-mediated repression of APC^Cdc20, which is responsible for the degradation of Securin to activate Separase and the degradation of Cyclin B to activate CDK1. Among these cell cycle controlling E3 ligases, APC^Cdh1 controls the ubiquitination and protein stability of Cdc20 and Skp2, thus ensuring the ordered activation and inactivation of APC/C and SCF in different cell cycle phases.