The Cell Cycle NOTES

Overview of Cell Division

The ability of organisms to reproduce their kind is the one characteristic that best distinguishes living
things from nonliving matter.
The continuity of life is based on the reproduction of cells, or cell division.

Cell division functions in reproduction, growth, and repair.

In the asexual reproduction of a unicellular organism, cell division organism reproduces an entire
organism, increasing the population.
Cell division on a larger scale can produce offspring for some asexually reproducing multicellular
organisms (such as plants that can grow from cuttings).
Cell division enables a multicellular organism to growth and develop from a single fertilized egg (or
zygote) into a full patterned adult.
In a multicellular organism, cell division functions to repair and renew cells that die from normal wear
and tear (for example, shedding your skin cells) or accidents (for example, a cut in your skin).

Cell division results in genetically identical daughter cells

Cell division requires the distribution of identical genetic material—DNA—to two daughter cells.
What is remarkable is the fidelity with which DNA is passed along, without dilution, from one
generation to the next.
A dividing parent cell replicates its DNA, separates the two identical copies to opposite ends of the cell,
and then splits into two daughter cells, each containing an identical, complete set of DNA.
A cell’s genetic information, packaged as DNA, is called its genome.
In prokaryotes (such as bacteria), the genome is usually a single long circular DNA molecule.
In eukaryotes (such as plants and animals), the genome consists of several long linear DNA
molecules packaged into chromosomes.
DNA molecules are packaged into chromosomes.
Every eukaryotic species has a characteristic number of chromosomes in each cell nucleus.
 Human somatic cells (body cells) are diploid, and have 46 total chromosomes, made up of two
sets of 23 (one from each parent).
 Human gametes (sperm or eggs) are haploid, and have one set of 23 chromosomes, half the
number in a somatic cell.
Eukaryotic chromosomes are made of chromatin, a complex of a long piece of DNA wrapped around
associated proteins.
Each single chromosome contains one long, linear DNA molecule carrying hundreds or thousands of
genes, the units that specify an organism’s inherited traits.
The associated proteins maintain the structure of the chromosome and help control gene activity.
When a cell is not dividing, each chromosome is in the form of a long, thin chromatin fiber.
Before cell division, chromatin condenses, coiling and folding to make a smaller package.
Each duplicated chromosome consists of two sister chromatids, which contain identical copies of the
chromosome’s DNA.
The condensed sister chromatids are initially attached by adhesive proteins at the centromere.
Later in cell division, the sister chromatids are pulled apart and repackaged into two new nuclei at
opposite ends of the parent cell.
Once the sister chromatids separate, they are considered individual chromatids or chromosomes.
 Mitosis, the formation of the two daughter nuclei, is usually followed by division of the cytoplasm,
cytokinesis.
These processes start with one parent cell and produce two daughter cells that are genetically identical
to the original parent cell and to each other.
Each of us inherited 23 chromosomes from each parent: one set in an egg and one set in sperm.
The fertilized egg, or zygote, underwent cycles of mitosis and cytokinesis to produce a fully
developed multicellular human made up of 200 trillion somatic cells.
These processes continue every day to replace dead and damaged cells.
Essentially, these processes produce clones—cells with identical genetic information.
In contrast, gametes (eggs or sperm) are produced only in gonads (ovaries or testes) by a variation of
cell division called meiosis.
Meiosis yields four nonidentical daughter cells, each with half the chromosomes of the parent.
In humans, meiosis reduces the number of chromosomes from 46 to 23.
Fertilization fuses two gametes together and doubles the number of chromosomes to 46 again.

Overview of the cell cycle

The mitotic (M) phase of the cell cycle alternates with the much longer interphase.
The M phase includes mitosis and cytokinesis.
Interphase accounts for 90% of the cell cycle.
During interphase, the cell grows by producing proteins and cytoplasmic organelles, copies its
chromosomes by DNA replication, and prepares for cell division.
Interphase has three subphases: the G1 phase (“first gap”), the S phase (“synthesis”), and the G2 phase
(“second gap”).
During all three subphases, the cell grows by producing proteins and cytoplasmic organelles such as
mitochondria and endoplasmic reticulum.
However, chromosomes are duplicated only during the S phase.
A typical human cell might divide once every 24 hours.
Of this time, the M phase would last less than an hour, while the S phase might take 10–12 hours, or
half the cycle.
The rest of the time would be divided between the G1 and G2 phases.
The G1 phase varies most in length from cell to cell.
Mitosis is a continuum of changes during which the nucleus of the parent cell splits and the replicated
DNA is divided equally between two daughter nuclei.
Mitosis is usually described as having five phases: prophase, prometaphase, metaphase, anaphase,
and telophase (SEE ALSO PHASES OF MITOSIS NOTES AS POSTED ON OUR WIKI).
In late interphase, the chromosomes have been duplicated but are not condensed.
A nuclear membrane bounds the nucleus, which contains one or more nucleoli.
The centrosome has replicated to form two centrosomes.
In animal cells, each centrosome features two centrioles.
In prophase, the chromosomes are tightly coiled, with sister chromatids joined together at their
centromeres.
The nucleoli disappear.
The mitotic spindle begins to form.
 It is composed of centrosomes and the microtubules that extend from them.
The radial arrays of shorter microtubules that extend from the centrosomes are called asters.
The centrosomes move away from each other, apparently propelled by lengthening microtubules.
During prometaphase, the nuclear envelope breaks down and disappears, and microtubules from the
spindle attach to the centromeres of the condensed sister chromatids.
 Each of the two sister-chromatids has a kinetochore, a specialized protein structure located at the
centromere to which the microtubules attach.
The spindle fibers push the sister chromatids until they are all arranged at the metaphase plate, an
imaginary plane across the middle of the parent cell, defining metaphase.
At anaphase, the centromeres divide, separating the sister chromatids.
Each individual chromatid is pulled toward the pole to which it is attached by spindle fibers.
By the end, the two opposite poles of the parent cell have equivalent collections of chromosomes.
At telophase, daughter nuclei begin to form at the two poles.
Nuclear envelopes reform around each daughter nucleus.
The chromosomes become less tightly coiled.
Cytokinesis, division of the cytoplasm, is usually well underway by late telophase.
In animal cells, cytokinesis involves the formation of a cleavage furrow, which pinches the cell in
two.
In plant cells, vesicles derived from the Golgi apparatus produce a cell plate at the middle of the cell.

The cell cycle is regulated by a molecular control system

The timing and rates of cell division in different parts of an animal or plant are crucial for normal
growth, development, and maintenance.
The frequency of cell division varies with cell type.
Some human cells divide frequently throughout life (skin cells).
Others have the ability to divide, but keep it in reserve (liver cells).
Mature nerve and muscle cells do not appear to divide at all after maturity.
Investigation of the molecular mechanisms regulating these differences provide important insights into
the operation of normal cells, and may also explain cancer cells escape controls.
The cell cycle appears to be driven by specific chemical signals present in the cytoplasm.
The sequential events of the cell cycle are directed by a distinct cell cycle control system.
Cyclically operating molecules trigger and coordinate key events in the cell cycle.
The control cycle has a built-in clock, but it is also regulated by external adjustments and internal
controls.
A checkpoint in the cell cycle is a critical control point where stop and go-ahead signals regulate the
cycle.
The signals are transmitted within the cell by signal transduction pathways.
Animal cells generally have built-in stop signals that halt the cell cycle at checkpoints until
overridden by go-ahead signals.
Many signals registered at checkpoints come from cellular surveillance mechanisms.
These indicate whether key cellular processes have been completed correctly.
Checkpoints also register signals from outside the cell.

Three major cell cycle checkpoints are found in the G1, G2, and M phases.
o At the G1  S checkpoint the cell is checked for damage to the DNA, appropriate cell size, and the
presence of necessary nutrients an d growth factors. If the cell passes this checkpoint is enters S
phase (DNA synthesis phase).
o At the G2  M checkpoint the cell is checked for damage to the DNA, complete and accurate DNA
replication and appropriate cell size. If the cell passes this checkpoint it enters M phase (mitosis).
o At the metaphase  anaphase checkpoint the cell is checked for attachment of the spindle fibers
to the kinetochores at centromeres of each sister chromatid and for proper alignment of the sister
 chromatides across the middle of the parent cell. If the cell passes this checkpoint, it will complete
cycokinesis and generate two daughter cells.

The three cell cycle checkpoints in detail

For many cells, the G1  S checkpoint, is the most important.
If the cell receives a go-ahead signal at the G1  S checkpoint, it usually completes the cell cycle
and divides.
If it does not receive a go-ahead signal, the cell exits the cycle and switches to a nondividing state,
the G0 phase.
 Most cells in the human body are in the G0 phase.
 Liver cells can be “called back” to the cell cycle by external cues, such as growth factors released
during injury.
 Highly specialized nerve and muscle cells never divide.
Rhythmic fluctuations in the abundance and activity of cell cycle control molecules pace the events of
the cell cycle.
These regulatory molecules include protein kinases that activate or deactivate other proteins by
phosphorylating them.
These kinases are present in constant amounts but require attachment of a second protein, a cyclin, to
become activated.
Levels of cyclin proteins fluctuate cyclically.
Because of the requirement for binding of a cyclin, the kinases are called cyclin-dependent kinases,
or Cdks.
Cyclin levels rise sharply throughout interphase, and then fall abruptly during mitosis.
Peaks in the activity of one cyclin-Cdk complex, MPF, correspond to peaks in cyclin concentration.
MPF (“maturation-promoting factor” or “M-phase-promoting-factor”) triggers the cell’s passage past
the G2  M checkpoint to the M phase.
MPF promotes mitosis by phosphorylating a variety of other protein kinases.
MPF stimulates fragmentation of the nuclear envelope by phosphorylation of various proteins of
the nuclear lamina.
It also triggers the breakdown of cyclin, dropping cyclin and MPF levels during mitosis and
inactivating MPF.
 The noncyclin part of MPF, the Cdk, persists in the cell in inactive form until it associates with
new cyclin molecules synthesized during the S and G2 phases of the next round of the cycle.
At least three Cdk proteins and several cyclins regulate the key G1  S checkpoint.
Similar mechanisms are also involved in driving the cell cycle past the metaphase  anaphase
checkpoint.
The metaphase  anaphase checkpoint ensures that all the chromosomes are properly attached to
the spindle at the metaphase plate before anaphase.
This ensures that daughter cells do not end up with missing or extra chromosomes.
A signal to delay anaphase originates at kinetochores that have not yet attached to spindle
microtubules.
This keeps the anaphase-promoting complex (APC) in an inactive state.
When all kinetochores are attached, the APC activates, triggering breakdown of cyclin and
inactivation of proteins holding sister chromatids together.

Internal and external cues help regulate the cell cycle.

While research scientists know that active Cdks function by phosphorylating proteins, the identity of all
these proteins is still under investigation.
 Scientists do not yet know what Cdks actually do in most cases.
Some steps in the signaling pathways that regulate the cell cycle are clear.
Some signals originate inside the cell, others outside.
A variety of external chemical and physical factors can influence cell division.
For example, cells fail to divide if an essential nutrient is left out of the culture medium.
Particularly important for mammalian cells are growth factors, proteins released by one group of cells
that stimulate other cells to divide.
For example, platelet-derived growth factors (PDGF), produced by platelet blood cells, bind to
tyrosine-kinase receptors of fibroblasts, a type of connective tissue cell.
This triggers a signal-transduction pathway that allows cells to pass the G1 checkpoint and divide.
Each cell type probably responds specifically to a certain growth factor or combination of factors.
The role of PDGF is easily seen in cell culture.
Fibroblasts in culture will only divide in the presence of a medium that also contains PDGF.
In a living organism, platelets release PDGF in the vicinity of an injury.
The resulting proliferation of fibroblasts helps heal the wound.
At least 50 different growth factors can trigger specific cells to divide.
The effect of an external physical factor on cell division can be seen in density-dependent inhibition of
cell division.
Cultured cells normally divide until they form a single layer on the inner surface of the culture
container.
If a gap is created, the cells will grow to fill the gap.
At high densities, the amount of growth factors and nutrients is insufficient to allow continued cell
growth.
Most animal cells also exhibit anchorage dependence for cell division.
To divide, they must be anchored to a substratum, typically the extracellular matrix of a tissue.
Control appears to be mediated by pathways involving plasma membrane proteins and elements of
the cytoskeleton linked to them.
Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence.

Cancer cells have escaped from cell cycle controls.

Cancer cells divide excessively and invade other tissues because they are free of the body’s control
mechanisms.
Cancer cells do not stop dividing when growth factors are depleted.
This is either because a cancer cell manufactures its own growth factors, has an abnormality in the
signaling pathway, or has an abnormal cell cycle control system.
If and when cancer cells stop dividing, they do so at random points, not at the normal checkpoints in
the cell cycle.
Cancer cells may divide indefinitely if they have a continual supply of nutrients.
In contrast, nearly all mammalian cells divide 20 to 50 times under culture conditions before they
stop, age, and die.
Cancer cells may be “immortal.”
HeLa cells from a tumor removed from a woman (Henrietta Lacks) in 1951 are still reproducing in
culture.
The abnormal behavior of cancer cells begins when a single cell in a tissue undergoes a transformation
that converts it from a normal cell to a cancer cell.
Normally, the immune system recognizes and destroys transformed cells.
However, cells that evade destruction proliferate to form a tumor, a mass of abnormal cells.
If the abnormal cells remain at the originating site, the lump is called a benign tumor.
Most do not cause serious problems and can be fully removed by surgery.
In a malignant tumor, the cells become invasive enough to impair the functions of one or more organs.
In addition to chromosomal and metabolic abnormalities, cancer cells often lose attachment to nearby
cells, are carried by the blood and lymph system to other tissues, and start more tumors in an event
called metastasis.
Cancer cells are abnormal in many ways.
They may have an unusual number of chromosomes, their metabolism may be disabled, and they
may cease to function in any constructive way.
Cancer cells may secrete signal molecules that cause blood vessels to grow toward the tumor.
Treatments for metastasizing cancers include high-energy radiation and chemotherapy with toxic drugs.
These treatments target actively dividing cells.
Chemotherapeutic drugs interfere with specific steps in the cell cycle.
For example, Taxol prevents mitotic depolymerization, preventing cells from proceeding past
metaphase.
The side effects of chemotherapy are due to the drug’s effects on normal cells.
Researchers are beginning to understand how a normal cell is transformed into a cancer cell.
The causes are diverse, but cellular transformation always involves the alteration of genes that
influence the cell cycle control system.