The Anaphase-Promoting Complex (APC/C) is a cellular machine found in all eukaryotic cells. It is composed of 11 to 13 protein subunits and plays a fundamental role in orchestrating cell division. This complex functions as a specialized enzyme that marks specific proteins for destruction, ensuring that cellular events proceed in an orderly and irreversible manner. The APC/C’s activity is tightly regulated, guiding cell cycle events, especially chromosome separation and new cell formation. Its proper operation is essential for maintaining cellular integrity and preventing errors.
The Cell Cycle’s Orchestrator
The APC/C exerts its influence particularly during the mitotic phase, which involves nuclear division and the division of the cytoplasm. The complex ensures that cells progress accurately through distinct stages, specifically controlling the transition from metaphase to anaphase and the subsequent exit from mitosis.
During metaphase, chromosomes align at the cell’s center, preparing for separation. The APC/C remains inhibited by a surveillance mechanism called the spindle assembly checkpoint until all chromosomes are correctly attached to the spindle microtubules. Once this attachment is confirmed, the checkpoint is silenced, allowing the APC/C to become active. This activation triggers the onset of anaphase, where sister chromatids—identical copies of chromosomes—are pulled apart to opposite ends of the cell.
The APC/C also promotes the exit from mitosis, facilitating the cell’s transition into the G1 phase, the period of growth before DNA replication. This precise timing prevents critical errors in chromosome segregation, which could otherwise lead to genetic abnormalities.
How APC/C Works
The APC/C functions as an E3 ubiquitin ligase, an enzyme that tags specific proteins with ubiquitin. This tagging, called ubiquitination, signals the protein for degradation. Ubiquitinated proteins are then broken down by the 26S proteasome.
The APC/C’s activity is controlled by activator subunits, primarily Cdc20 and Cdh1, which help the complex recognize and bind to its target proteins. For instance, at the metaphase-anaphase transition, the APC/C, in conjunction with Cdc20 (APC/CCdc20), targets securin for degradation. Securin normally inhibits an enzyme known as separase.
Once securin is degraded, separase becomes active and cleaves cohesin, a protein complex that holds sister chromatids together. This cleavage allows the sister chromatids to separate and move to opposite poles of the cell, marking the beginning of anaphase.
The APC/C also targets mitotic cyclins, such as cyclin B, for degradation. Degradation of cyclin B inactivates mitotic cyclin-dependent kinases (M-CDKs), which maintain the mitotic state. This inactivation allows the cell to exit mitosis and complete cell division.
Maintaining Cellular Balance
The accurate and tightly regulated activity of the APC/C maintains cellular health and genetic stability. Its precise control over protein degradation ensures that cell division proceeds without errors. This coordinated breakdown of regulatory proteins prevents premature or delayed progression through the cell cycle, which could otherwise lead to severe consequences for the cell.
A primary function of the APC/C is to ensure the correct segregation of chromosomes during cell division. By properly timing the separation of sister chromatids, the APC/C helps prevent aneuploidy, a condition where cells have an abnormal number of chromosomes. Aneuploidy can arise from chromosome mis-segregation and is generally detrimental to cell function.
The APC/C also contributes to maintaining the integrity of the genome by ensuring that DNA replication occurs only once per cell cycle. Its sustained activity in the G1 phase, often in association with Cdh1 (APC/CCdh1), keeps the levels of S-phase cyclins low, preventing premature entry into DNA replication. This continuous control safeguards against genomic instability, which is a hallmark of many diseases.
When APC/C Malfunctions
Dysregulation of the Anaphase-Promoting Complex can have consequences for cellular function and organismal health. When APC/C activity is either too high or too low, it can lead to uncontrolled cell division or, conversely, to cell death. These imbalances often contribute to the development and progression of various diseases.
A well-established link exists between APC/C dysfunction and cancer. Errors in APC/C activity can lead to chromosomal instability, a condition characterized by frequent changes in chromosome number and structure. For example, overexpression of Cdc20, an APC/C activator, has been associated with numerous cancers, including prostate, breast, and bladder cancers. This overexpression can allow cancer cells to bypass cell cycle checkpoints, leading to uncontrolled proliferation.
Conversely, mutations in APC/C subunits, such as CDC27, can also impact cancer progression. Understanding the precise mechanisms of APC/C dysregulation in different cancers opens avenues for potential therapeutic strategies. For instance, drugs that modulate APC/C activity or target specific pathways influenced by its dysfunction are being explored as potential treatments to restore proper cell cycle control in cancerous cells.