THE CELL CYCLE – ITS PHASES, EVENTS AND REGULATION

The cell cycle is an ordered process during which a eukaryotic cell undergoes cell growth, DNA replication and finally divides into two identical daughter cells. All organisms begin their life from a single cell. The cell cycle allows formation of multiple cells from a single one.

The cell cycle occurs in a sequence of four phases. The interphase comprises of three stages, G₁, G₂ and S phase. The interphase lasts more than 95% of the duration of cell cycle. During interphase, a cell grows in size and does DNA replication. Interphase is followed by the M (mitosis) phase during which karyokinesis (division of nuclear material by separation of daughter chromosomes) and cytokinesis (division of cytoplasm) occur.

Such a cycle needs to be monitored throughout to ensure that cells with only appropriate function divide to generate healthy, functional daughter cells. The cell cycle is regulated primarily by cyclins and cyclin dependent kinases.

PHASES OF CELL CYCLE

The cell cycle can be divided into an interphase (G₁, G₂, S) and an M (mitosis) phase.

Some cells, like cardiac cells and neurons do not exhibit cell division. These cells enter a quiescent stage called G₀ . Cells in this stage remain metabolically active but no longer proliferate unless it is required.

G1 (GAP 1 / GROWTH 1) PHASE

This is the longest phase of interphase. Following events occur during this phase:

• Cell growth
• Duplication of cellular content except chromosome
• Transcription
• Translation

The checkpoint at G₁ evaluates whether the cell size, DNA integrity and available nutrients are adequate to progress to the next stage.

S (SYNTHESIS) PHASE

DNA replication occurs during S phase. The amount of DNA per cell doubles during this phase. However, there is no increase in the chromosome number.

G₂ (GAP 2 / GROWTH 2) PHASE

Following events occur during this phase:

• Rapid cell growth
• Protein synthesis (translation)
• Duplication of organelles like mitochondria, lysosomes and plastids
• Synthesis of microtubule required for formation of spindle fibers which are essential for segregating chromosomes.

The checkpoint at G₂ monitors for DNA damage and repairs any errors. If there is any error in DNA replication, cell will not enter the next phase of mitosis.

M (MITOSIS) PHASE

The M phase follows the interphase. During this phase, the cell divides into two identical daughter cells. It involves two main processes: karyokinesis (division of nucleus) and cytokinesis (division of cytoplasm).

Mitosis is known as equational division as the number of chromosomes in the parent and progeny cell is the same.

Mitosis is divided into following four stages:

• PROPHASE – Chromatin condenses into chromosomes.
• METAPHASE – Chromosomes arrange linearly at the equator.
• ANAPHASE – Chromosomes separate at the centromere and start moving to opposite poles
• TELOPHASE – Chromosomes unwind into chromatin. Nuclear membrane reforms. Nucleoli reappear.

The cytoplasm then divides.

REGULATION OF CELL CYCLE

Cell cycle regulation is the mechanism that ensures proper growth and division of cell. It is primarily managed by cyclins and cyclin dependent kinases (CDK).

CDKs are enzymes that get activated when they bind to specific cyclins. The fluctuation in levels of cyclins during various phases of cell cycle has been shown in above graph. Cyclin D binds CDK 4 and CDK 6, cyclin E binds CDK 2, cyclin A binds CDK 1 and 2, cyclin B binds CDK 1.

There are three major checkpoints during the course of cell cycle – at end of G₁ , end of G₂ and during M phase. Progression through checkpoints is regulated by cyclins, CDKs and tumor suppressors.

In the presence of growth factors, there is synthesis of cyclin D. Cyclin D interacts with CDK 4/6 and activates it. On the DNA, Rb protein (a tumor suppressor) binds with E2F transcription factor and prevents expression of E2F. The active CDK 4/6 phosphorylates Rb protein which causes degradation of Rb protein and E2F gets expressed.

Level of cyclin E then rises and it bind to CDK 2 to activate it. Increased levels of cyclin E inhibits p27 (repressor of cyclin E and CDK 2). The cell then progresses into the S phase.

During the S phase there is MCM activation and DNA replication. Cyclin A – CDK 2 is required for DNA synthesis. Cyclin A – CDK 1 and cyclin B – CDK 1 promote the events of mitosis.

Towards the end of mitosis, the anaphase promoting complex causes ubiquitination and destruction of cyclin A – CDK 1 and cyclin B – CDK 1 leading to termination of M phase.