Cell cycle refers to the process of division marked by cell growth, DNA replication, distribution of replicated chromosomes to daughter cells, followed by cell division that a cell undergoes proliferation. It consists of different phases, regulated by the cell cycle checkpoints. There are a group of enzymes and proteins that regulate and ensure the replication of DNA and cell division linking to the extracellular signals to control cell proliferation. Any defective DNA is immediately repaired, and, if unrepairable, it leads to programmed cell death (apoptosis). These proteins are, in turn, controlled by proto-oncogenes and oncogenes, whose mutation leads to cancer.
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BU-Bio7-cell-cycle

Image: “BU Bio7” by Elapied. License: CC BY-SA 2.0 FR


Introduction to Cell Cycle

Cell cycle or cell division is a sequence of events appearing in a eukaryotic cell related to its division, DNA replication, and equal distribution of chromosomes in two daughter cells and the production of two daughter cells. The cell division is enhanced by two types – Mitosis and Meiosis. Mitosis is a type of cell division characterized by the production of two daughter cells with the same number of chromosomes in their nuclei, whereas meiosis is characterized by production of four cells with half number (haploid) of chromosomes in their four nuclei.

The cell cycle is a vital phenomenon which leads to the formation of a fully developed organism from a single fertilized egg. The cell cycle also plays a significant role in the further regeneration of new cells in a fully grown organism.

Stages of Cell Cycle

The cell cycle has two main phases which are further divided into distinct stages. The two main phases include:

Interphase

  • G1 phase
  • S phase (Synthesis)
  • G2 phase

Mitotic (M) Phase

  • Karyokinesis
  • Cytokinesis

G0 is another phase where the cells have left the cell cycle temporarily and reversibly. It is a quiescent phase where the cell remains metabolically active but do not grow or proliferate. The cells do not divide during this phase. It has reduced rates of protein synthesis. It can also be called the resting phase of the cell cycle.

A summary of events taking place during these phases is tabulated below:

Phase Events
G1 (Gap 1) Cell prepares for DNA replication, and cell grows
S (Synthesis) DNA replication occurs
G2 (Gap 2) Cell grows and prepares for final cell division
M (Mitosis) Cell divides into two daughter cells

The duration of phases of the cell cycle varies in different kinds of cells. Each phase is dependent on other for fruitful completion of the cell cycle by activation and regulation processes. This restriction is managed and controlled by cell cycle checkpoints present at different phases of a cycle.

Cell Cycle Checkpoints

Cell-Cycle-checkpoints

Image: “Schematic of the cell cycle. Outer ring: I = Interphase, M = Mitosis; inner ring: M = Mitosis; G1 = Gap phase 1; S = Synthesis; G2 = Gap phase 2. The duration of mitosis in relation to the other phases has been exaggerated in this diagram” by Zephyris. License: CC BY-SA 3.0

The cell cycle is monitored and controlled by certain regulatory proteins called cell cycle checkpoints. These checkpoints are present at certain critical areas of the cycle to ensure that the previous phase has completed without any error or whether any repair is needed. Once all the necessary repairs of the previous phase have been completed, only then these checkpoints allow the cell to proceed to the next phase.

There are three checkpoints in each cell cycle:

  1. G1/S Checkpoint
  2. G2/M Checkpoint
  3. Metaphase Checkpoint

G1/S Checkpoint

G1/S checkpoint, also called restriction point, is the first integral checkpoint of the cell cycle located between G1 and S phase. This checkpoint ensures that the cell has all the essential nutrients to undergo DNA replication. This checkpoint decides whether the cell should remain inG1 phase, enter G0 phase, or proceed to S phase.

This decision is based on both internal and external factors. A cell with any deficiency or defect that may hinder the DNA replication will not be allowed to go beyond this stage into S phase.

G2/M Checkpoint

After the cell undergoes successful DNA replication in S phase and is growing in G2 phase, this checkpoint assesses:

  • If the DNA replication was successful and there lies any need to repair defective replicated DNA or not.
  • An adequate amount of cytoplasm and phospholipids are present for the cell to undergo complete division into two daughter cells.
  • If it is the right time for the cell to proceed to mitosis phase for the final division.

The G2/M checkpoint is regulated by M-phase promoting factor (MPF) that consists of a group of enzymes and proteins called cyclin-CDK complex.

Cell-Cycle-With-Cyclins-and-Checkpoints

Image: “0332 Cell Cycle with Cyclins and Checkpoints” by OpenStax. License: CC BY 4.0

Metaphase Checkpoint (Spindle Checkpoint)

Once the cell is in metaphase, this checkpoint ensures:

  • If the mitotic spindle has formed and,
  • If the chromosomes have aligned themselves at the mitotic plate and adequate tension exists in the spindles.

The presence of tension in the spindles ensures there is no inhibition of anaphase-promoting complex (APC/C) and thus the cell enters the next stage, anaphase.

Cyclin-Expression-cell-cycle

Image: “Cyclin Expression” by WikiMiMa. License: Public Domain

Cell Cycle Checkpoints – A Cyclically Activated Protein Kinase System

The cell cycle checkpoints consist of a group of protein kinases called cyclin-dependent kinases (CDK). The activity of these CDKs is controlled by an array of enzymes and proteins collectively referred to as cyclins. This cyclin-CDK complex is the basis of the checkpoints that regulate the cell cycle.

The activity of CDKs oscillates throughout the cell cycle, thus, leading to cyclic phosphorylation of proteins that initiate, regulate, or inhibit the events of the cell cycle.

Eukaryotic cells require three among four classes of cyclins to bind to CDKs:

  • G1/S cyclins (bind to CDKs at the end of G1 phase and let the cell decide for DNA replication)
  • S-Cyclins (bind CDKs during S phase and initiate DNA replication)
  • M-Cyclins (regulate and promote events of mitosis)

Cyclin-CDK complexes that are at play during different phases and checkpoints of the cell cycle are:

Phase

Cyclin

CDK

G1

D, E

Cdk2, Cdk4, Cdk6

S

A, E

Cdk2

G2

A

Cdk1, Cdk2

M

B

Cdk1

Checkpoints and their Cyclin-CDK Complexes

G1/S Checkpoint and Cyclin-CDKs

CDKs-breast-cancer-cell-cycle

Image: “Cyclin D1, CDK4 and p16 expression in invasive ductal breast carcinomas analyzed by immunohistochemistry. (B) High nuclear cyclin D1 expression. (D) High nuclear CDK4 expression. (F) High p16 expression. (A), (C) and (E) are negative controls for (B), (D) and (F), respectively.” by Peurala E, Koivunen P, Haapasaari KM, Bloigu R, Jukkola-Vuorinen A – Breast Cancer Res. (2013). License: CC BY 2.0

A rise in cyclin D stimulates its bondage to CDK4 and CDK6, and this complex result in phosphorylation of proteins. Meanwhile, accumulation of cyclin E induces the formation of a complex with CDK2 that stimulates the cell to enter an irreversible stage of DNA replication.

G2/M Checkpoint and cyclin-CDKs

At this checkpoint, cyclin B binds to CDK1 which, in turn, regulates the events and generates activation of subsequent proteins and the entry of the cell into the Mitotic phase.

During this stage, DNA damage is also assessed and in case of defective or incomplete DNA replication, activation of CDK1 and CDK2, along with p53, occurs to halt the cell cycle and prevent it from entering mitosis.

Metaphase/Spindle Checkpoint and cyclin-CDKs

The tension built within the spindles activates anaphase-promoting complex (APC) which degrades cyclin B and, in turn, causes breakdown of proteins (securing, separase, cohesin) which bind the chromosomes together.

Role of p53 Gene

Damaged DNA formed during a cell cycle stimulates the activation of the tumor suppressor gene called p53. Commonly known as “the guardian of genome,” this gene ensures that no cell transfers any damaged DNA into the daughter cells.

If a damaged DNA is sensed at G1/S checkpoint, it halts the cycle by activating CDK inhibitor (CKI) that temporarily stops the cell cycle by binding to cyclin-CDK complex until the DNA is repaired; thereby, it activates the production of DNA repairing enzymes. These enzymes repair the damaged DNA. If the repairing process fails, the p53 gene allows the cell to undergo programmed cell death.

In case of defective or absence of p53 gene, damaged and mutated DNA is passed on to the cells and leads to the development of cancer. Mutated p53 gene is responsible for healthy completion of the cell cycle.

Proto-Oncogenes

These genes regulate cell growth, differentiation, and proliferation, and tend to inhibit apoptosis. Any mutation in the gene or over-expression will stimulate them to transform into oncogenes, and eventually result in uncontrolled cell proliferation progressing to cancer.

Some proto-oncogenes include growth factors, RAS proteins, and Src kinase.

  • Growth factors induce cell proliferation. Growth factor receptors are increased in cases of breast cancer.
  • RAS protein is involved in signaling a pathway in cell proliferation. Mutation of RAS protein leads to myeloid leukemia, thyroid tumor, and adenocarcinoma of pancreas and colon. It is activated by mutation in 20 —30% of all cancers.
  • Src kinase regulates cell proliferation, migration, differentiation, and apoptosis. Its Mutation leads to head and neck cancers, brain cancers, etc. It is activated by a mutation in 2%—5% of all cancers.

Tumor-Suppressor Genes

These genes actively de-accelerate cell division, manage DNA repair and guides the cell towards apoptosis. Mutation in this gene will lead to the development of cancer because damaged DNA will accumulate in the cells preventing apoptosis.

Tumor-suppressor genes are grouped into caretaker genes, gatekeeper genes, and landscaper genes. Common tumor-suppressor genes include Retinoblastoma protein (pRb) and p53 gene.

pRB is mutated in 40% of all cancers, and p53 is mutated in 50% of all cancers.

Retinoblastoma-tumor-suppressor-cell-cycle

Image: “Schematic of the retinoblastoma tumor suppressor pathway” by Witkiewicz AK, Knudsen ES – Breast Cancer Res. (2014). License: CC BY 2.0

The Two-Hit Hypothesis

This hypothesis was first proposed by A.G. Knudson, This hypothesis states that two mutations should occur in both the tumor suppression genes to trigger cancer. If one allele is defective, the other one will still produce normal protein, and a cancerous tumor cannot be formed.

Thus this hypothesis indicates that mutated tumor-suppressor alleles are recessive (deactivated) while mutated oncogene alleles are dominant (activated) during cancer development.

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