The orderly reproduction of cells sustains life, enabling growth, tissue repair, and the maintenance of multicellular organisms. The cell cycle must be precisely coordinated to ensure that genetic material is duplicated and segregated accurately between two new daughter cells. Without stringent regulation, cells could divide uncontrollably or fail to pass complete genetic information, leading to dysfunction. A complex network of proteins acts like an internal biological timer, ensuring each step is completed before the next one can begin.
Stages of the Cell Cycle
The cell cycle is structured into four sequential phases. The longest part of this sequence is interphase, which includes the G1, S, and G2 phases. The G1 phase, or Gap 1, is a period of intense growth and metabolic activity where the cell accumulates resources and building blocks for division.
Following this initial growth, the cell enters the S phase, where DNA synthesis, or replication, takes place. Once DNA replication is complete, the cell moves into the G2 phase, another gap period where the cell continues to grow and synthesizes proteins required for the final division.
The final stage is the M phase, which encompasses both mitosis, the division of the nucleus, and cytokinesis, the separation of the cytoplasm. During mitosis, the replicated chromosomes are aligned and then separated to opposite poles of the cell. This process culminates in the formation of two genetically identical daughter cells.
Cyclins and Cyclin-Dependent Kinases
Progression through the cell cycle phases is governed by a partnership between two families of proteins: cyclins and cyclin-dependent kinases (CDKs). CDKs are enzymes that function as serine/threonine protein kinases and act as the cell cycle’s engine. CDKs are present throughout the entire cell cycle, but they remain functionally inactive in isolation.
Cyclins are the regulatory partners whose concentrations fluctuate across the different stages. A cyclin must bind to a specific CDK to form an active complex, which enables the CDK to phosphorylate target proteins. This phosphorylation acts like a switch, activating or deactivating the downstream proteins responsible for executing the tasks of a particular cell cycle phase. The periodic synthesis and destruction of cyclins drive the cell cycle forward.
Phase-Specific Timing of Cyclin Presence
The presence and activity of specific cyclin-CDK complexes are precisely timed to ensure that events like DNA replication and chromosome separation occur only once per cycle. The sequential activation of these complexes acts as the molecular clock of the cell.
G1 Phase and G1/S Transition
The cell’s commitment to division is regulated by the G1 cyclins, primarily Cyclin D, which accumulates in response to external growth signals. Cyclin D partners with Cyclin-Dependent Kinase 4 (CDK4) and Cyclin-Dependent Kinase 6 (CDK6) to form active complexes. These complexes initiate the phosphorylation of the retinoblastoma (Rb) protein, a tumor suppressor that normally keeps the cell cycle arrested.
The partial phosphorylation of Rb by Cyclin D/CDK4/6 releases transcription factors, allowing for the expression of the next set of regulatory proteins, including Cyclin E. Cyclin E then binds to Cyclin-Dependent Kinase 2 (CDK2) to form the Cyclin E/CDK2 complex. The activity of this complex peaks sharply at the boundary between G1 and S phase, driving the cell past the restriction point and committing it to DNA replication.
S Phase and G2 Phase
Once the cell enters the Synthesis phase, Cyclin E levels drop, and Cyclin A begins to accumulate and associate with CDK2. The resulting Cyclin A/CDK2 complex is responsible for initiating DNA replication. Cyclin A also helps maintain progression through S phase by preventing the re-replication of DNA that has already been copied.
As the cell moves into the G2 phase, Cyclin A continues to be active, but it transitions to binding with Cyclin-Dependent Kinase 1 (CDK1). This new Cyclin A/CDK1 complex, along with the subsequent mitotic cyclins, prepares the cell for the structural changes required for division.
M Phase
The entry into mitosis is primarily controlled by the accumulation of Cyclin B, which partners with CDK1. The resulting Cyclin B/CDK1 complex, historically known as maturation-promoting factor (MPF), accumulates through G2 and peaks at metaphase. Once fully activated, this complex phosphorylates numerous target proteins, leading to the breakdown of the nuclear envelope, the condensation of chromosomes, and the assembly of the mitotic spindle apparatus. This activity is maintained until the chromosomes are properly aligned and ready for segregation.
Checkpoints and Cyclin Degradation
The cell cycle is protected by monitoring mechanisms, known as checkpoints, which ensure that no phase is prematurely initiated. These checkpoints, such as the G2/M boundary, verify that the DNA is fully replicated and undamaged before allowing the activated cyclin-CDK complexes to drive the cell into mitosis. The rapid removal of cyclins is just as important as their synthesis for maintaining the one-way progression of the cycle.
Once a cyclin-CDK complex has completed its specific task, the cyclin subunit is marked for destruction through ubiquitination. Enzymes attach a small protein tag called ubiquitin to the cyclin molecule. This process acts as a signal that targets the cyclin protein to the proteasome, a cellular machine that breaks down unneeded or damaged proteins.
The Anaphase-Promoting Complex/Cyclosome (APC/C) is a major enzyme complex involved in this degradation, targeting Cyclins A and B near the end of mitosis to facilitate the exit from the M phase. The destruction of Cyclin B at the metaphase-to-anaphase transition allows the cell to separate its sister chromatids and complete the division process.