The cell cycle is the fundamental, highly organized process by which a cell grows, duplicates its genetic material, and divides into two daughter cells. This sequence of events requires precision to maintain the integrity of the genetic code. The Anaphase Promoting Complex (APC/C) serves as a master regulator, ensuring the cell moves forward through division stages only when all previous steps are complete. The APC/C provides an irreversible switch that drives the cell from one phase to the next, controlling the transition into chromosome separation and the subsequent exit from cell division.
Defining the Anaphase Promoting Complex and its Structure
The APC/C is a massive multi-subunit enzyme complex found in all eukaryotic organisms. Structurally, it is composed of 11 to 13 distinct protein subunits, making it one of the largest protein machines within the cell. This physical complexity allows it to integrate various regulatory signals before committing to its core function. Its primary biochemical identity is that of an E3 ubiquitin ligase, a specialized class of enzyme. The core catalytic activity resides in subunits like Apc2 (a cullin) and Apc11 (containing a RING finger domain), which facilitate the transfer of ubiquitin, a small regulatory protein, onto target molecules.
The Mechanism of Targeted Protein Destruction
The core mechanism of the APC/C is the precise and timely destruction of specific regulatory proteins that govern cell cycle progression. This is achieved through ubiquitination, the attachment of ubiquitin proteins to the target substrate. Acting as an E3 ligase, the APC/C recruits activated ubiquitin from an E2 enzyme and links it to a lysine residue on the target protein.
The APC/C builds a polyubiquitin chain, typically linked through the K11 residue of ubiquitin. This chain functions as a molecular tag, marking the protein for destruction. Once tagged, the substrate is recognized by the 26S proteasome, a cylindrical complex that acts as the cell’s recycling center, unfolding and degrading the protein into short peptides. This targeted degradation makes cell division irreversible, unlike a phosphorylation event.
The two most consequential initial targets are Securin and Mitotic Cyclins. Degradation of Securin releases Separase, a protease that cleaves the cohesin complexes holding sister chromatids together, initiating the physical separation of chromosomes. Simultaneously, the destruction of Mitotic Cyclins (such as Cyclin B) inactivates associated Cyclin-Dependent Kinases (CDKs), driving the cell out of mitosis.
The Two Critical Activation Phases
The destructive power of the APC/C is tightly controlled through its interaction with two mutually exclusive activator proteins, Cdc20 and Cdh1, which dictate the timing and substrate specificity. The binding of either co-activator determines which set of proteins is marked for degradation. This dual-activation system ensures a highly ordered sequence of events.
APC/C-Cdc20 Activation
The first phase of APC/C activity is driven by Cdc20 binding, forming the APC/C-Cdc20 complex. This complex becomes fully active only after all chromosomes have successfully attached to the spindle apparatus, a condition monitored by the Spindle Assembly Checkpoint (SAC). Once the SAC is satisfied, APC/C-Cdc20 rapidly targets Securin and Cyclin B for destruction. This synchronous degradation triggers anaphase (the separation of sister chromatids) and initiates mitotic exit.
APC/C-Cdh1 Activation
Following mitotic exit, the second phase is regulated by the co-activator Cdh1, forming the APC/C-Cdh1 complex. The transition to Cdh1 activation is linked to the drop in Cdk activity caused by Cyclin B destruction, which allows Cdh1 to be dephosphorylated and bind to the APC/C. The APC/C-Cdh1 complex remains active throughout late mitosis and the entire G1 phase. This complex maintains the G1 state by keeping Cdk activity low.
Its substrates include remaining mitotic cyclins, mitotic kinases (like Plk1), and importantly, the co-activator Cdc20 itself. By destroying Cdc20, the complex prevents the cell from re-entering mitosis prematurely, enforcing irreversible cell cycle progression.
APC/C Malfunction and Disease
Errors in APC/C function are directly linked to human disease, particularly cancer, due to its role as a core regulator of chromosome segregation. Dysregulation often leads to aneuploidy, where cells possess an incorrect number of chromosomes due to missegregation. This genomic instability drives tumor development by altering gene dosage.
The APC/C activators, Cdc20 and Cdh1, play distinct roles in cancer progression. Overexpression of Cdc20 is frequently observed in tumors, where it acts as an oncogene. High Cdc20 levels can overwhelm the Spindle Assembly Checkpoint, forcing premature division and increasing chromosome missegregation.
Conversely, the loss or inactivation of Cdh1 is also a common event in cancer, suggesting it acts as a tumor suppressor. When APC/C-Cdh1 activity is compromised, the cell fails to properly degrade mitotic proteins and enter a quiescent state, leading to uncontrolled proliferation and genomic instability. The APC/C is a promising target for novel anti-cancer therapies aimed at restoring its precise regulatory control.