Most cells divide periodically to give rise to two daughter cells. A cell cycle covers a period of time from one cell division to the next.

Phases of cell cycle

– First gap phase – G1 phase – cell grows in size and prepares for DNA replication. G1 checkpoint (see below) makes sure everything is ready for DNA replication. This is also the period where the cells carry out their normal metabolic roles for the body. 

– Synthesis phase – S phase – DNA replication occurs, the cell makes a second, identical set of DNA molecules. It now has two sets, ready to distribute to the two daughter cells.

– Second gap phase – G2 phase – preparation for cell division, cell synthesizes proteins/enzymes that are necessary for mitosis. G2 checkpoint (see below) makes sure the cell is ready for division.

– Proper cell division – M phase – mitosis phase where the mother cell is split into two daughter cells by the process of mitosis. Mitosis has four phases on its own : prophase, metaphase, anaphase and telophase (commonly with cytokinesis).

Fig. 1 : A typical cell cycle with four phases. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

 

 

 

 

The G1, G2 and S phases are together called interphase – the time in between M phases. The length of cell cycle varies greatly from one cell type to another with the length of G1 phase being most variable.

G0 (G zero) phase

In an adult multicellular organism, it’s very common for cells to stop dividing permanently or temporary for a certain period of time. Such cells are said to be in G0 phase (resting phase), or to be quiescent. They usually enter G0 phase from G1 phase (Fig. 2). Fully differentiated skeletal muscle cells and neurons are post-mitotic and stay in G0 for the rest of their life. Some other cells can be stimulated to get back to G1 when needed (e.g. liver cells). Finally, there are cells that never enter G0 and continue dividing for life (e.g. epithelial cells).

Fig. 2 : A cell cycle diagram showing exit to G0. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Cell cycle checkpoints

Checkpoints are control mechanisms to ensure that cell division proceeds with highest accuracy. Before going into the next phase, the cell has to check if everything is ready, scan for DNA damage and activate repair if needed. If the cell is not ready, cell cycle will be arrested. This is to ensure that damaged or incomplete DNA molecules are not passed onto daughter cells.

There are three main checkpoints in the cell cycle:

– G1 checkpoint ( also called restriction point in animal cell, or start point in yeast) is located at the end of G1 phase, before the entrance to S phase. This is the point when the cell needs to make a decision to divide or not depending on the environmental factors. The cell may proceed to cell division (to S phase), delay division waiting for more signals (stay in G1), or enter resting phase (to G0 phase).

– G2 checkpoint is located at the end of G2 phase, before commitment to M phase. Here the cell needs to check if everything is ready for mitosis. Most importantly, it has to check for any DNA damages that may have occurred during DNA synthesis (S phase). If damages are detected, cell cycle will be arrested at this point.

– Metaphase checkpoint (spindle checkpoint) is located in metaphase, before the onset of anaphase. This is to make sure that ALL the chromosomes are properly aligned at the metaphase plate before the sister chromatids can be pulled apart in anaphase. If a chromosome is “late” to come to its position, the metaphase will be arrested waiting for it. This is how the cell ensures that the two daughter cells will have exactly the same set of chromosomes. Failure of this would result in a daughter cell with an extra chromosome and the other missing a chromosome, a situation that is deleterious for both.

Molecular regulators of cell cycle

Cyclins and cyclin-dependent kinases (CDKs) form cyclin-CDK complexes that determine the progression of cell cycle through different phases. Cyclins are regulatory subunits of the complexes and are expressed only at specific stages of cell cycle. CDKs are catalytic subunits of the complexes and are activated by binding to cyclins. Upon binding to a cyclin, CDK acquires ability to phosphorylate target proteins. CDKs are constitutively expressed. Combination of different CDKs to different cyclins determine substrate specificity of the complexes.

Inhibitors of cell cycle or tumor suppressors – a class of molecules that prevent the progression of the cell cycle. Many of these arrest the cell cycle in G1 phase by binding to and inactivating cyclin-CDK complexes.

Regulation of cell cycle and cancer

The number of cells in a tissue is determined by the balance between cell division and cell death. The proportion of cells actively dividing versus those in resting (G0) phase plays an important role and must be strictly controlled. Disregulation of cell cycle would result in uncontrollable cell division and formation of abnormal growths called tumors. Tumors that can spread to other organs are cancers. Cancerous cells are characterized by an inability to stop diving and to enter resting phase.