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Cell Cycle

The cell cycle or cell division cycle is a set of events that ensure the division of a cell into two daughter cells.

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A cell is the unit of life. To maintain continuity in life, cells have to keep dividing. Growth of an individual and repair of injuries also require cell division.

Before a cell can divide, it has to ensure the following things:

  1. It has sufficient nutrients (growth signals) to grow.
  2. It has replicated its genetic material (DNA).
  3. It has no damage to its DNA.

A cell goes through the cell cycle to ensure a successful cell division.

Phases of the cell cycle

The cell cycle is an ordered series of events that results in the division of a cell into two daughter cells. It is composed of 4 stages (phases).

  1. G1 phase (growth phase 1)
  2. S phase (synthesis phase)
  3. G2 phase (growth phase 2)
  4. M phase (mitosis or division phase)

If the cell does not have enough resources to grow, it can exit the cell cycle into a resting phase called G0 (I pronounce it as G naught).

The first three phases of the cell cycle - G1, S and G2 are together called interphase. So, cells spend most of their time in interphase, growing and replicating their DNA, before dividing in the M phase.

Diagram of the cell cycle showing the 4 different phases and the G0 phase, with short descriptions of the main event in each phase.
Diagram of the cell cycle phases. The 4 cell cycle phases G1, S, G2 and M are shown. The G0 phase, which cells enter when they stop dividing, is also shown. © Sampath Amitash Gadi.

Let us understand a bit more about each cell cycle phase.

G1 Phase

In the G1 phase of the cell cycle, a cell prepares to replicate it DNA. Growth factors in the surrounding medium called mitogens can be recognised by receptors on the cell surface. This allows the cell to grow by producing more mRNA and proteins. mRNA is produced by transcription of DNA. This mRNA is used to produce proteins by a process called translation.

These proteins are also called cell cycle regulators. Key proteins in this category are the cyclins and cyclin dependent kinases (CDKs). Cyclins and CDKs are considered to be the main drivers of the cell cycle. They are the positive regulators of the cell cycle. On the contrary, negative regulators of the cell cycle also exists. For example, the cell cycle checkpoints negatively regulate the cell cycle.

Specific CDKs are activated by their partner cyclins. Activated CDKs are enzymes that can catalyse the addition of a phosphoryl group (PO3) to other proteins. This is called phosphorylation.

In G1, cyclin D is the main cyclin. It activates CDK4/6 which phosphorylates the retinoblastoma protein (Rb).

Phosphorylation of Rb is a positive signal for the cell cycle to proceed. It signals the production of cyclin E, which activates CDK2. This is a signal for the cell to proceed to the next phase, the S phase or synthesis phase.

CDK2 activity removes a negative regulator of the cell cycle, APC/C (anaphase promoting complex/cyclosome). APC/C promotes the anaphase stage of mitosis but needs to be removed in G1, for the cell to proceed into S phase. Removal of APC/C is a restriction point in the cell cycle. Once APC/C is removed, cells are irreversibly committed to enter S phase, replicate their DNA and divide into two daughter cells.

In G1, cells also prepare for DNA replication by identifying and marking origins of replication. In organisms like humans which have a huge genome, cells require multiple origins of replication to replicate their DNA.

Diagram depicting the activation of a cyclin-dependent kinase by its partner cyclin.
Cyclin-dependent kinases (CDKs) are the drivers of the cell cycle. CDKs are activated by their partner cyclins. © Sampath Amitash Gadi.

S Phase

In the S phase of the cell cycle, DNA is replicated to produce a duplicate of the genome. DNA replication uses the cell’s DNA as a template to synthesise a new, identical copy of DNA.

CDK2 activated at the end of G1 pushes cells in to S phase by promoting initiation of DNA replication.

After the end of S phase, the diploid chromosomes (46 in number) doubles to become 92.

The human genome sequence is 3.2 billion base pairs long. In S phase, this entire DNA sequence is copied to create an identical, duplicate DNA sequence.

In complex genomes such as ours, DNA is replicated from multiple origins of replication. At each origin, double-stranded DNA is unwound in to two single-stranded DNA molecules. Each of these single-stranded DNA is used as a template to synthesise a complementary strand of DNA. The newly synthesised daughter DNA strands will be an identical copy of the parental DNA template.

G2 Phase

After DNA replication is completed, cells continue to grow in the G2 phase. Cells prepare to segregate the duplicated DNA. This process is also mediated by CDKs.

In G2, CDK2 activity peaks and induces the production of cyclin B (G2 cyclin). Cyclin B activates CDK1, which prepares cells for mitosis by activating proteins required for mitosis.

Mitosis

In mitosis, chromosomes duplicated in S phase can finally segregate into two daughter cells.

Mitosis is divided into substages:

  1. Prophase - DNA starts to condense into chromosomes
  2. Prometaphase - Thread like fibres called the spindle are formed and bind to chromosomes
  3. Metaphase - DNA is fully condensed and are visible as chromosomes
  4. Anaphase - chromosomes are segregated into two opposite sides of the cell using spindle fibres
  5. Telophase - a nucleus forms around chromosomes at each side of the cell

Cytokinesis

After mitosis, two nuclei are formed in the cell. Such a cell is called a binucleate cell.

After telophase and during cytokinesis, a binucleate cell divides into two daughter cells. This completes the cell cycle. The newly formed daughter cells can enter a new cell cycle.

Diagram depicting the stages of the cell cycle with focus on mitosis and a brief description of each stage.
Mitosis is the last phase of the cell cycle. In mitosis, DNA duplicated in S phase is organised into chromosomes. These chromosomes are eventually segregated into two daughter cells. The substages of mitosis are also indicated. © Sampath Amitash Gadi.

Cell Cycle Checkpoints

A cell cycle checkpoint is a cellular signalling pathway that pauses the cell cycle in events of distress. This is mediated by checkpoint proteins including cyclins and CDKs. Another popular cell cycle checkpoint protein is p53.

Checkpoints exist at different phases of the cell cycle.

A checkpoint exists during the G1/S transition. This checkpoint monitors for DNA damage during the transition of the cell cycle from G1 to S phase. If this checkpoint point is activated, cells will be arrested in G1 and will not enter S phase. The G1 checkpoint is also mediated by CDKs and p53. Long-term arrest of the cell cycle will lead to the activation of a cell suicide program called apoptosis.

However, once the G1 checkpoint is passed, the cell is irreversibly committed to division. This means, a cell that crossed the G1 checkpoint cannot enter G0 phase.

The checkpoint that monitors DNA replication in S phase is called the intra-S-phase checkpoint. It ensures that no ‘gaps’ are left behind during DNA synthesis.

In G2, a checkpoint is activated if any unreplicated or damaged DNA was detected. This is the G2 checkpoint. It halts the cell cycle and recruits DNA repair proteins to the damaged DNA. Once DNA damage is repaired, checkpoint signalling stops and the cell cycle can resume.

The checkpoint in mitosis is called the M checkpoint or the spindle checkpoint. It checks for proper chromosome arrangement. It also ensures that the spindle fibres are attached to the chromosomes, for proper segregation.

Here is a summary of the cell cycle checkpoints.

G1/S checkpoint

  • Monitors for growth signals and cell size
  • Monitors origins of replication and DNA damage

Intra S checkpoint

  • Monitors for DNA damage during replication

G2 checkpoint

  • Monitors for unreplicated and damaged DNA

M checkpoint (spindle checkpoint)

  • Monitors for proper chromosome arrangement
  • Monitors for correct spindle fibre attachment

Diagram depicting the checkpoints in a cell cycle with a brief description of what each checkpoint monitors.
The cell cycle checkpoints. Each checkpoint acts as a quality check to ensure the cell is ready for the next phase of the cell cycle. © Sampath Amitash Gadi.

Cell Cycle Duration

The duration of each phase of the cell cycle varies in different kinds of cells.

A typical human cell cycle lasts about 24 hours. G1 lasts from 9 to 11 hours. S phase lasts from 8 to 10 hours. G2 for about 4 hours and Mitosis for about an hour.

Interphase is the longest phase of the cell cycle.

Summary

In this article, I have presented an introductory overview of the cell cycle. I briefly described the phases of the cell cycle and what happens in each phase. Furthermore, I also introduced how the cell cycle is regulated by cyclins, CDKs and other regulators of the cell cycle. I then introduced cell cycle checkpoints and how they act as quality control checks before a cell divides. These checks help to avoid passing of mutations to the next generation.

This article is intended for readers who are just getting started to learn about the cell cycle. I hope to have provided a comprehensive overview of the cell cycle.

Authors

Sampath Amitash Gadi, Ph.D.
Author

Sampath Amitash Gadi, Ph.D.

Sampath works as a DNA researcher at the University of Copenhagen. His research deals with how proteins and signaling among proteins help to counter DNA Damage in human cells.