Phoenix Mombru

Describe the process of cell division and how defects in the process can lead to cancer

In eukaryotes, cell division is regulated by the cell cycle. The tight control of the cell cycle
ensures that cells only divide when required, eliminating the excessive cell division which
may lead to tumour formation. It also ensures that, if errors are spotted during DNA
replication or other processes during the cycle, the cell can be made to undergo apoptosis,
again reducing the risk that harm may be caused to the organism by mutations or DNA
damage. However, this process can be defective. In this essay I will begin by describing the
process of cell division before discussing three defects in the cell cycle which may lead to
cancer: errors in chromosome segregation which may lead to aneuploidy; inhibition of Rb co-
repressor proteins by cancer viruses which allow the cell to divide in the absence of
mitogens; and failure of the cell cycle checkpoints, leading to faulty cell division which could
result in formation of cancerous tumours.

Cell division and the cell cycle

The cell cycle consists of four phases: G1, S, G2 and M, with an additional phase, G0,
representing quiescence, a rest phase outside of the cell cycle. External signals known as
mitogens stimulate the cell to pass from G0 phase to G1. During G1, the cell grows and
synthesises the proteins required to carry out DNA synthesis. At a certain point in G1, the cell
passes a Restriction point, where the cell commits to progress through the whole cell cycle.
Hyperphosphorylation of Rb co-repressor proteins is required for the cell to pass through this
point. Next, the cell enters S phase, where DNA is replicated. The next phase is G2 phase,
where the cell grows more and responds to internal cues which ensure that the replicated
DNA is prepared for mitosis. The final phase, M phase, or mitosis, is where the cell divides.
This occurs in five stages: prophase, prometaphase, metaphase, anaphase and telophase. After
mitosis, cytokinesis occurs.

During prophase, the chromosomes, duplicated during S phase, condense. The centrosomes,
where the mitotic spindle is organised, migrate to the poles of the cell and begin to assemble
microtubules. During prometaphase, the nuclear envelope breaks down into vesicles,
allowing the spindle microtubules to attach to the centromeres of the chromosomes via a
protein complex called the kinetochore. During metaphase, the chromosomes line up along
the equator of the cell, connected to each centrosome by one microtubule. During anaphase,
the sister chromatids are pulled apart by the two microtubules, requiring the breakdown of
cohesion. During telophase, the chromosomes arrive at their respective poles of the cell and
new nuclear membranes form around each of the two groups of chromosomes. Finally,
cytokinesis occurs, with the cytoplasm of the parent cell constricting at opposing ends until it
splits to form two identical daughter cells.

Defects in chromosome segregation

Replication of DNA during S phase can lead to supercoiling of DNA, which is resolved by
topoisomerases which nick the DNA, allowing strands to unravel from each other, and
rotation of chromosomes. These processes result in sister chromatids becoming intertwined.
Additionally, a ring-shaped protein called cohesin holds together the sister chromatids.
During mitosis, a Spindle Assembly Checkpoint ensures that the chromosomes are properly
aligned. If only one microtubule is attached to the chromosome, then no tension will be
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generated so the sister chromatids will not be pulled to either side. This ensures that the
chromatids are not separated before both spindle fibres attach, however the presence of an
inappropriate number of centrosomes, such as three centrosomes, can lead to aneuploidy as
there will not be enough chromatids to go to each ‘pole’ of the cell. Before the chromatids
can be pulled apart, the cohesin holding the chromatids together must be degraded. A
protease called separase cleaves cohesin, separating the sister chromatids. Separase is kept in
an inactive state through phosphorylation by cyclin dependant kinase (CDK) and by binding
to an inhibitor called securing. A complex called anaphase promoting complex (APC) binds
to a protein called Cdc20 and ubiquitinates both cyclin B (decreasing the action of CDK) and
securing, leading to their ubiquitin-mediated degradation. This activates separase which
cleaves securing, separating the sister chromatids. Failure to separate the sister chromatids
may result in both chromatids being pulled to the same side of the cell, causing aneuploidy in
both mitotic daughter cells. Cells with aneuploidy have an increased risk of developing
cancer, with 90% of cancers being aneuploid, as the abnormal set of chromosomes would
result in general genomic instability and malfunction.

Defects in Rb protein action

The cell cycle is regulated by proteins called cyclins. Cyclin E is associated with the G1
phase of the cell cycle, and the expression of the cyclin E gene is necessary for the cell to
pass the Restriction point of G1 and pass through the rest of the cell cycle. External signals
called mitogens, which include growth factors, stimulate the cell to express cyclin E and,
therefore, commit to passing through the cell cycle. The cyclin E gene is expressed through
the action of the E2F1 transcription factor. Normally this transcription factor is inhibited by a
repressor protein known as Rb. Additionally, the E2F4 repressor protein, which is bound to
the p107 co-repressor protein, is bound to the cyclin E gene to prevent E2F1 binding.
Mitogens activate cyclin D, which is bound to CDK4. CDK4 phosphorylates the Rb and p107
corepressors so that E2F4 is removed from the cyclin E gene and E2F1, no longer repressed
by Rb, can bind to and transcribe the gene, promoting cyclin E synthesis and passage of the
cell past the Restriction point. It has been found that cancers can result from mutations that
allow cell division in the absence of mitogens, for example through mutation of mitogen
receptors such as the epidermal growth factor receptor (EGFR) which would allow
inappropriate passage of the cell through the cell cycle and, therefore, uncontrolled and
prolific cell division which would lead to cancer. Several cancer-causing viruses also inhibit
Rb, allowing E2F1 to transcribe the cyclin E gene, for example HPV which can cause
cervical cancer and SV40, which can cause cancer in humans and apes.

Defects at the cell cycle checkpoints

As well as the Spindle Assembly Checkpoint (SAC) mentioned previously, there are two
other cell cycle checkpoints: the G2/M checkpoint which checks that cells have replicated
completely before undergoing mitosis, and the G1/S checkpoint, which checks for DNA
damage before allowing cells to undergo DNA replication. At the G2/M checkpoint,
checkpoint kinases, including ATM/ATR and Chk1/Chk2, stabilise and activate Wee1 kinase
and repress Cdc25 phosphatase. Wee1 kinase phosphorylates the cyclin B/CDK1 complex,
deactivating it, which Cdc25 phosphatase dephosphorylates it, inactivating it. Errors in this
process could lead to inappropriate activation of the cyclin B/CDK1 complex, which
facilitates passage of the cell into M phase, again leading to uncontrolled and prolific cell
division which could lead to cancer.
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At the SAC, APC-Cdc20 activation, which leads to degradation of cohesin, is prevented until
the chromosomes are correctly attached to the spindle as a complex known as mitotic
checkpoint complex (MCC) binds to and inhibits Cdc20. Defects in this process could, as
described for erroneous chromosome segregation, lead to aneuploidy, which would greatly
increase risk of cancer.

In conclusion, the process of cell division is controlled and regulated by the cell cycle, which
consists of G1, S, G2 and M phases. Mitosis consists of five phases: prophase, prometaphase,
metaphase, anaphase and telophase, and is followed by cytokinesis. Errors in the process of
cell division which could lead to cancer include defective chromosome segregation during
mitosis which could lead to aneuploidy, defective control of the Rb co-repressor protein and
the mitogenic pathway, which could lead to uncontrolled cell division and defective control at
the cell cycle checkpoints, which could lead to both uncontrolled cell division and
aneuploidy.