Anaphase-promoting Complex - M To G1 Transition

M To G1 Transition

Upon completion of mitosis, it is important that cells (except for embryonic ones) go through a growth period, known as G1 phase, to grow and produce factors necessary for the next cell cycle. Entry into another round of mitosis is prevented by inhibiting Cdk activity. While different processes are responsible for this inhibition, an important one is activation of the APC/C by Cdh1. This continued activation prevents the accumulation of cyclin that would trigger another round of mitosis and instead drives exit from mitosis.

In the beginning of the cell cycle Cdh1 is phosphorylated by M-Cdk, preventing it from attaching to APC/C. APC/C is then free to attach to Cdc20 and usher the transition from metaphase to anaphase. As M-Cdk gets degraded later in mitosis, Cdc20 gets released and Cdh1 can bind to APC/C, keeping it activated through the M/G1 transition. A key difference to note is that while binding of Cdc20 to APC/C is dependent on phosphorylation of APC/C by mitotic Cdks, binding of Cdh1 is not. Thus, as APCCdc20 becomes inactivated during metaphase due to dephosphorylation resulting from inactive mitotic Cdks, Cdh1 is able to immediately bind to APC/C, taking Cdc20’s place. Cdc20 is also a target of APC/CCdh1, ensuring that APC/CCdc20 is shut down. APC/CCdh1 then continues working in G1 to tag S and M cyclins for destruction. However, G1/S cyclins are not substrates of APC/CCdh1 and therefore accumulate throughout this phase and phosphorylate Cdh1. By late G1, enough of the G1/S cyclins have accumulated and phosphorylated Cdh1 to inactivate the APC/C until the next metaphase.

Once in G1, APCCdh1 is responsible for the degradation various proteins that promote proper cell cycle progression. Geminin is a protein that binds to Cdt1 which prevents its binding to the origin recognition complex (ORC). APCCdh1 targets geminin for ubiquitination throughout G1, keeping its levels low. This allows Cdt1 to carry out its function during pre-RC assembly. When APCCdh1 becomes inactive due to phosphorylation of Cdh1 by G1/S cyclins, geminin activity is increased again. Additionally, Dbf4 stimulates Cell division cycle 7-related protein kinase (Cdc7) activity, which promotes activation of replication origins. APCCdh1 is thought to target Dbf4 for destruction. This could provide an answer as to how Cdc7 is activated at the beginning of a new cell cycle. Its activity likely corresponds to the inactivation of APC/CCdh1 by G/S cyclins.