Cell division, or mitosis, is a tightly orchestrated process fundamental to life, requiring cells to duplicate and distribute their genetic material with precision. At the heart of this regulation is the Anaphase-Promoting Complex/Cyclosome (APC/C), a large protein complex that acts as a controller during the late stages of mitosis. The APC/C’s role is to ensure that key transitions happen in the correct order and only when the cell is ready.
It governs the irreversible step into anaphase, the stage where duplicated chromosomes are pulled apart. By controlling the destruction of specific proteins, the APC/C dictates the flow of events, safeguarding the accurate partitioning of the genome into two new daughter cells.
The Spindle Assembly Checkpoint Prerequisite
The APC/C does not operate in isolation; its activity is held in check by a surveillance system called the Spindle Assembly Checkpoint (SAC). The SAC acts as a “wait” signal during metaphase, inspecting the mitotic spindle, which is the apparatus of protein fibers responsible for pulling chromosomes apart. The SAC’s primary function is to ensure every chromosome is properly attached to the spindle.
It specifically monitors the connection points on chromosomes, known as kinetochores. If even one kinetochore remains unattached, the SAC sends out an inhibitory signal that directly blocks the APC/C. This “stop” command is generated by checkpoint proteins that assemble into the Mitotic Checkpoint Complex (MCC). This MCC binds to the APC/C, preventing it from acting and giving the cell time to correct attachment errors. Only when all chromosomes achieve a stable, bipolar attachment is the SAC satisfied and silenced, allowing the MCC to disassemble and the APC/C to become active.
Activating Anaphase Through Securin Degradation
Once the Spindle Assembly Checkpoint gives the “go” signal, the active APC/C targets its first substrate, a protein named securin. The destruction of securin is the direct trigger for anaphase. This process involves three molecular players: cohesin, separase, and securin. Cohesin is a protein complex that acts like molecular glue, holding the two identical sister chromatids together.
To initiate anaphase, this cohesin glue must be cut by a protease called separase. Throughout early mitosis, separase is kept inactive because it is bound by its inhibitor, securin, ensuring chromatids remain linked until the cell is ready. The active APC/C breaks this stalemate by marking securin for destruction.
With securin eliminated, separase is liberated and becomes active. The freed separase then cleaves the cohesin complexes, dissolving the link between the chromatids. This allows the mitotic spindle to pull the now-independent chromatids to opposite poles of the cell, an event that defines the beginning of anaphase.
Facilitating Mitotic Exit by Degrading Cyclins
After triggering chromosome separation, the APC/C’s job is not finished. For the cell to complete its division and return to a non-dividing state, it must exit mitosis. This requires dismantling the mitotic environment, a task orchestrated by the APC/C through the degradation of its second major target class: mitotic cyclins. These proteins, particularly Cyclin B, are drivers of the mitotic state.
Mitotic cyclins partner with enzymes called cyclin-dependent kinases (CDKs) to form active complexes. The Cyclin B-CDK1 complex phosphorylates hundreds of proteins, promoting events like chromosome condensation and mitotic spindle formation. As long as Cyclin B-CDK1 activity is high, the cell remains locked in a mitotic state.
To reverse this, the APC/C marks mitotic cyclins for destruction. As cyclins are degraded, CDK activity plummets, which is the overarching signal for the cell to exit mitosis. This triggers a cascade of dephosphorylation events, including:
- The disassembly of the mitotic spindle
- The decondensation of chromosomes
- The reformation of the nuclear envelope (telophase)
- The final division of the cytoplasm (cytokinesis)
The Mechanism of Protein Degradation
The APC/C marks proteins for destruction using the ubiquitin-proteasome system. The APC/C is an E3 ubiquitin ligase, an enzyme that identifies specific target proteins and facilitates the attachment of ubiquitin, a small protein, to them. First, a ubiquitin-activating enzyme (E1) prepares a ubiquitin molecule in an energy-dependent step. The activated ubiquitin is then transferred to a ubiquitin-conjugating enzyme (E2).
The E3 ligase—in this case, the APC/C—acts as a matchmaker. It recognizes and binds to both its specific substrate, like securin, and the E2 enzyme carrying the ubiquitin. The APC/C then catalyzes the transfer of ubiquitin from the E2 to a lysine residue on the target protein.
This action is repeated to create a polyubiquitin chain on the substrate, which functions as a degradation signal. This chain is recognized by the 26S proteasome, a large protein complex that acts as the cell’s protein disposal machinery. The proteasome captures the tagged protein, unfolds it, and feeds it into its central chamber where it is chopped into small peptide fragments.
Consequences of APC/C Malfunction
The precise timing and regulation of the APC/C are necessary for maintaining genomic stability. Errors in APC/C activity can lead to a failure in proper chromosome segregation, resulting in daughter cells with an incorrect number of chromosomes—a condition known as aneuploidy.
If the APC/C activates prematurely, before the Spindle Assembly Checkpoint is satisfied, sister chromatids can be pulled apart before they are all correctly attached to the spindle. This can lead to some chromatids lagging behind or being pulled to the wrong pole. Conversely, if the APC/C fails to activate, the cell becomes permanently arrested in metaphase, unable to degrade securin and cyclins, and may ultimately undergo cell death.
Both scenarios can result in aneuploidy, which is a characteristic of many human cancers and the underlying cause of genetic disorders such as Down syndrome. A dysfunctional APC/C can lead to genomic instability, promoting tumor development and resistance to therapy.