The Cell Cycle

A eukaryotic cell cannot divide into two, the two into four, etc. unless two processes alternate:

• doubling of its genome (DNA) in S phase (synthesis phase) of the cell cycle;
• halving of that genome during mitosis (M phase).

The period between M and S is called G₁; that between S and M is G₂. 

So, the cell cycle consists of:

• G₁ = growth and preparation of the chromosomes for replication;
• S = synthesis of DNA [see DNA Replication] and duplication of the centrosome;
• G₂ = preparation for
• M = mitosis.

When a cell is in any phase of the cell cycle other than mitosis, it is often said to be in interphase.

Control of the Cell Cycle

The passage of a cell through the cell cycle is controlled by proteins in the cytoplasm. Among the main players in animal cells are:

• Cyclins
• G₁ cyclins (D cyclins)
• S-phase cyclins (cyclins E and A)
• mitotic cyclins (B cyclins)

Their levels in the cell rise and fall with the stages of the cell cycle.

• Cyclin-dependent kinases (Cdks)
• a G₁ Cdk (Cdk4)
• an S-phase Cdk (Cdk2)
• an M-phase Cdk (Cdk1)

Their levels in the cell remain fairly stable, but each must bind the appropriate cyclin (whose levels fluctuate) in order to be activated.

They add phosphate groups to a variety of protein substrates that control processes in the cell cycle.

• The anaphase-promoting complex (APC). (The APC is also called the cyclosome, and the complex is often designated as the APC/C.) The APC/C
• triggers the events leading to destruction of cohesin (as described below) thus allowing the sister chromatids to separate;
• degrades the mitotic (B) cyclins.

Steps in the cycle

• A rising level of G₁-cyclins bind to their Cdks and signal the cell to prepare the chromosomes for replication.
• A rising level of S-phase promoting factor (SPF) — which includes A cyclins bound to Cdk2 — enters the nucleus and prepares the cell to duplicate its DNA (and its centrosomes).
• As DNA replication continues, cyclin E is destroyed, and the level of mitotic cyclins begins to rise (in G₂).
• M-phase promoting factor (the complex of mitotic [B] cyclins with the M-phase Cdk [Cdk1]) initiates

assembly of the mitotic spindle

breakdown of the nuclear envelope

cessation of all gene transcription

condensation of the chromosomes

• These events take the cell to metaphase of mitosis.
• At this point, the M-phase promoting factor activates the anaphase-promoting complex (APC/C) which
• allows the sister chromatids at the metaphase plate to separate and move to the poles (= anaphase), completing mitosis.

Separation of the sister chromatids depends on the breakdown of the cohesin that has been holding them together. It works like this. §  Cohesin breakdown is caused by a protease called separase (also known as separin). §  Separase is kept inactive until late metaphase by an inhibitory chaperone called securin. §  Anaphase begins when the anaphase promoting complex (APC/C) destroys securin (by tagging it with ubiquitin for deposit in a proteasome) thus ending its inhibition of separase and allowing §  separase to break down cohesin.

• destroys B cyclins. This is also done by attaching them to ubiquitin which targets them for destruction by proteasomes.

• turns on synthesis of G₁ cyclins (D) for the next turn of the cycle.
• degrades geminin, a protein that has kept the freshly-synthesized DNA in S phase from being re-replicated before mitosis.

Some cells deliberately cut the cell cycle short allowing repeated S phases without completing mitosis and/or cytokinesis. This is called endoreplication and is described on a separate page. Link to it.

Meiosis and the Cell Cycle

The special behavior of the chromosomes in meiosis I requires some special controls. Nonetheless, passage through the cell cycle in meiosis I (as well as meiosis II, which is essentially a mitotic division) uses many of the same players, e.g., MPF and APC. (In fact, MPF is also called maturation-promoting factor for its role in meiosis I and II of developing oocytes.

Checkpoints: Quality Control of the Cell Cycle

The cell has several systems for interrupting the cell cycle if something goes wrong.

• DNA damage checkpoints. These sense DNA damage both before the cell enters S phase (a G₁ checkpoint) as well as after S phase (a G₂ checkpoint).
• Damage to DNA before the cell enters S phase inhibits the action of Cdk2 thus stopping the progression of the cell cycle until the damage can be repaired (with the aid of BRCA2). If the damage is so severe that it cannot be repaired, the cell self-destructs by apoptosis.
• Damage to DNA after S phase (the G₂ checkpoint), inhibits the action of Cdk1 thus preventing the cell from proceeding from G₂ to mitosis.
• A check on the successful replication of DNA during S phase. If replication stops at any point on the DNA, progress through the cell cycle is halted until the problem is solved.

• spindle checkpoints. Some of these that have been discovered
• detect any failure of spindle fibers to attach to kinetochores and arrest the cell in metaphase until all the kinetochores are attached correctly (M checkpoint — example);
• detect improper alignment of the spindle itself and block cytokinesis;