R02.7: The Cell Cycle

The cell cycle describes the stages through which a cell passes through as it replicates. The length of time a cell may take to complete the cell cycle is highly variable; in mammals the time varies from 10 hours to 10 days. A commonly used hamster cell line has a cell cycle time of 24 hours.
The basic division of the cell cycle is into that of mitosis and interphase. Cells may also be in a special state known as G0 or ‘resting phase’, where the cell is not making any effort to divide. Most terminally differentiated cells are in this phase.

Phases of the Cell Cycle


Interphase is the period between when a cell has just divided until it divides again. It has three phases – Gap 1 (G1), Synthesis (S) and Gap 2 (G2).

G1 is the phase following mitosis and preceding the synthesis phase. It is the most variable part of the cell cycle – lasting at least one hour and over 100 hours in some dividing cells. It is the main contributor to the length of the cell cycle. Part of this gap is to allow the cell to duplicate its organelles (such as ribosomes, endoplasmic reticulum). The other reason the gap exists is to monitor external and internal signals to identify whether division should proceed. A checkpoint exists at the end of the G1 phase which is designed to delay progression into the S phase until the environment is ideal for replication.
The synthesis phase is when DNA is duplicated into two sister chromatids. The cell requires two complete sets of all 46 chromosomes (one set for each daughter cell). This is performed by DNA polymerase and other enzymes, which divide the DNA helix into two separate strands and then assemble a new set of base pairs for each. The copying of DNA takes between 6-10 hours in most cells.
The G2 gap, which occurs after DNA synthesis and before mitosis, is usually short (1-3 hours). It allows the cell to confirm that the DNA has been replicated correctly and that other conditions have been met to allow it to proceed to M phase. A G2 checkpoint exists to facilitate this.

Mitosis and Cytokinesis

M phase is the period where the cell actively divides into two daughter cells. It takes approximately one hour in nearly all cells, regardless of the total cell cycle time (Hall & Giaccia, 2005). There are two related events – mitosis and cytokinesis. Mitosis is subdivided into several events:

  • Prophase – The cell begins to assemble the mitotic spindle, a set of microtubules extending from the centromeres which will later attach to the chromosomes.
  • Prometaphase – The nuclear envelope disintegrates, and the microtubules of the mitotic spindle attach to the chromosomes.
  • Metaphase – The chromosomes are aligned on the mitotic spindle. There is a pause here to allow all chromosomes to become attached.
  • Anaphase – The cohesion proteins which bind the sister chromatids together are cleaved and the chromosomes are pulled apart by the mitotic spindle.
  • Telophase – The nuclear membrane reconstitutes around each set of chromosomes.

Cytokinesis completes the M phase. It begins during anaphase, with the cell membrane forming a contractile ring perpendicular to the metaphase plate. Organelles are distributed more or less equally to the two daughter cells. During the end of telophase, the cell completes division and two daughter cells are created. Cells do not always undergo cytokinesis, instead forming multinucleate giant cells. This can be a normal event or can be due to errors in mitosis.

Cell Cycle Regulators

The cell cycle is under strict control in most cells, the mechanics of which are somewhat understood. There are a number of proteins involved in the regulation of the cell cycle, the speed at which it traverses the various stages, and the various checkpoints which help to control these.

As a basic summary, there are various levels of machinery which allow the cell cycle to take place.
At the most basic level, there are the cyclin dependent kinases that, when activated, turn on progression through the cell cycle
Above this are the cyclins, molecules which are released in response to the various stimuli to activate the CDKs
Another level of proteins control activation of the cyclins. This is when it starts getting very complicated! There are proteins which stimulate progression through the cell cycle (such as MYC), and proteins which halt progression (such as RB1 and TP53).
There are hundreds of factors which can influence the pro- and anti-cell cycle progression pathways, either by themselves or by setting in motion a cascade of enzyme activations.

Cyclin Dependent Kinases (CDK)

These are proteins which become active when a cyclin protein binds to them. There are multiple types but only several are involved in the cell cycle. CDK4 and CDK6 are involved in G1 phase, CDK2 in G1 and S phase, and CDK1 in G2 and mitosis. Once bound with cyclin, CDKs require phosphorylation to function. This is performed by the cell division cycle phosphatases (see below). Once activated, CDKs are involved in activating a downstream chain of proteins which promote progression through the cell cycle. CDKs are usually present in the cell at similar concentrations throughout the entire cell cycle, relying on cyclins to become active.


Cyclins are small molecules which attach to the various CDK molecules to allow them to act. These molecules are produced by the cell to promote progression through the cell cycle, and there are several types:

  • D-Cyclins are not present during G0, but become activated when the cell receives signals to divide. They bind to CDK 4 and CDK 6 and promote progressions through G1.
  • E-Cyclins become active at the end of G1 and bind to CDK 2. They are important for progression from G1 to S phase. The E-CDK2 complex is degraded by the SPC ubiquitin ligase during S-phase.
  • α-cyclins bind with both CDK 1 and 2. The α-CDK2 complex is required to progress through S phase. The α-CDK1 complex promotes progression through G2 phase, and is thought to promote chromatin condensation. This complex is destroyed by APC (anaphase promoting complex) in the prometaphase.
  • β-cyclins bind with CDK 1. The resulting complex becomes active during the prophase stage of mitosis. It is involved in centromere separation as well as other mitotic events. Once activated, the β–CDK1 complex also inactivates the molecules which inhibit its expression, allowing a large amount of β–CDK1 to become active quickly. β –CDK1 is also destroyed by the anaphase promoting complex (APC).

Cell Division Cycle Phosphatases (CDC)

In humans, there are multiple types of Cell Division Cycle Phosphatases (cdc) that are relevant for control of the cell cycle. Three important molecules include cdc25A, cdc25B and cdc25C. They function by removing phosphate groups from the various cyclin/CDK complexes, allowing them to become active. They are important targets for control of the cell cycle, as their removal will render the CDK complexes inactive despite the presence of cyclin.

Cyclin Dependent Kinase Inhibitors (CDKI)

This is a group of kinases which (in general) inhibit the production or function of the CDKs. There are two major families:

  • The INK4 group of CDKIs consist of four proteins which inhibit the binding of cyclin D to CDK 4 and 6.
  • The CIP/KIP group of proteins bind to and inhibit the function of cyclin-E/CDK2 and cyclin-α/CDK2 complexes. An important member of this group is p21, which in turn is activated by p53 (below).

Retinoblastoma Protein 1 (RB1)

The RB1 gene was first identified in children with familial retinoblastoma. Its protein functions as a tumour suppressor gene by binding to and thereby inhibiting a family of proteins known as E2F. These proteins promote the production of cyclins (E and α) as well as DNA replication proteins. Rb normally exists bound to E2F; the cyclin-D/CDK4&6 and cyclin-E/CDK2 complexes cause phosphorylation of Rb and change its configuration, releasing the E2F protein which then leads to progression of the cell cycle.

Tumour Protein P53 (TP53)

TP53 is an important protein which helps to regulate many stages of the cell cycle. It is located at the centre of a number of pathways related to DNA repair, apoptosis, angiogenesis and cell cycle arrest. Two important activators are the ATM/CHK2 pathway (triggered by DNA damage) and the p19ARF pathway (triggered by oncogene activation). The loss of p53, a common occurrence in human tumours, leads to deregulation of the cell cycle. Li-Fraumeni syndrome, a genetic condition caused by mutation in the p53 gene, leads to multiple tumours developing throughout the body.