HANDOUTS (OCTOBER 3-6, 2022)

CELL CYCLE- is a series of events that takes place inn a cell as it grows and
divides. A cell spends most of its time in what is called INTERPHASE, and during
this time it grows, replicates its chromosomes, and prepares for cell division. The cell
then leaves interphase, undergoes MITOSIS, and completes its cell division. The
resulting cells, known as DAUGHTER CELLS, each enter their own interphase and
begin a new round of cell cycle.

The ability to produce in kind is a basic characteristic of all living

organisms. In kind means that the offspring of any organism closely resemble their
parent or parents. Sexual reproduction requires fertilization, the union of gametes
from two individual organisms resulting in a fertilized egg or zygote. Countless cell
divisions subsequently occurs in a controlled manner to produce a complex,
multicellular organism. In other words, that original single cell is the ancestor of every
other cell in the body. Once an individual is fully grown, cell reproduction is still
necessary to repair or regenerate tissues. For example, new blood and skin cells
are constantly being produced. All multicellular organisms use cell division for
growth and for the maintenance and repair of cells and tissues. For single-celled
organisms, they use cell division as their method of reproduction.

Cell division is just one of several stages that a cell goes through during its
lifetime. The continuity of life from one cell to another has its foundation in the
reproduction of cells by way of the cell cycle.
The cell cycle is a repeating series of events that include growth, DNA synthesis,
and cell division. The cell cycle in prokaryotes is quite simple: the cell grows, its DNA
replicates, and the cell divides. In eukaryotes, the cell cycle is more complicated.

 Eukaryotic Cell Cycle

The diagram in Figure 1 below represents the cell cycle of a eukaryotic cell.
As you can see, the eukaryotic cell cycle has several phases. The mitotic phase
(M) actually includes both mitosis and cytokinesis. This is when the nucleus and then
the cytoplasm divide. The other three phases (G1, S, and G2) are generally grouped
together as interphase. During interphase, the cell grows, performs routine life
processes, and prepares to divide. These phases are discussed below.
 Eukaryotic Cell Cycle. This diagram represents the cell cycle in eukaryotes.
The First Gap, Synthesis, and Second Gap phases make up interphase (I). The M
(mitotic) phase includes mitosis and cytokinesis. After the M phase, two cells result.
Interphase
Interphase of the eukaryotic cell cycle can be subdivided into the following
three phases, which are represented in Figure above:
• Growth Phase 1 (G1): during this phase, the cell grows rapidly, while
performing routine metabolic processes. It also makes proteins needed for DNA
replication and copies some of its organelles in preparation for cell division. A cell
typically spends most of its life in this phase. This phase is also known as gap
phase 1 or First Gap.
• Synthesis Phase (S): during this phase, the cell’s DNA is copied in the
process of DNA replication. This phase is also known as Synthesis of DNA.
• Growth Phase 2 (G2): during this phase, the cell makes final
preparations to divide. For example, it makes additional proteins and organelles.
This phase is also known as gap phase 2 or Second Gap.
 Control Points of the Cell Cycle
If the cell cycle occurred without regulation, cells might go from one phase to
the next before they were ready. What controls the cell cycle? How does the cell
know when to grow, synthesize DNA, and divide? The cell cycle is controlled mainly
by regulatory proteins. These proteins control the cycle by signaling the cell to either
start or delay the next phase of the cycle. They ensure that the cell completes the
previous phase before moving on. Regulatory proteins control the cell cycle at key
checkpoints, which are shown in Figure 2 below. There are a number of main
checkpoints.

Figure 2 Control Points of the Cell Cycle

Checkpoints in the eukaryotic cell cycle ensure that the cell is ready to
proceed before it moves on to the next phase of the cycle.
• The G1 checkpoint, just before entry into S phase, makes the key
decision of whether the cell should divide. At this point, the cell also checks for DNA
damage. A cell that does not meet all the requirements will not progress to the S
phase. The cell can halt the cycle and attempt to remedy the problematic condition,
or the cell can advance into G0 (inactive) phase and await further signals when
conditions improve.
• The S Checkpoint Synthesis Phase (S): during this phase, the cell’s
DNA is copied in the process of DNA replication. This phase is also known as
Synthesis of DNA.
• The G2 Checkpoint determines if the DNA has been replicated
properly. If the checkpoint mechanisms detect problems with the DNA, the cell cycle
is halted and the cell attempts to either complete DNA replication or repair the
damaged DNA. If the DNA has been correctly replicated, cyclin dependent kinases
(CDKs) signal the beginning of mitotic cell division.
• The M checkpoint/ Mitotic Spindle checkpoint occurs at the point in
metaphase where all the chromosomes should have aligned at the mitotic plate.
 Regulator Molecules of the Cell Cycle
The cell cycle is controlled by regulator molecules that either promote the
process or stop it from progressing. These regulatory molecules either promote
progress of the cell to the next phase (positive regulation) or halt the cycle (negative
regulation). Regulator molecules may act individually or they can influence the
activity or production of other regulatory proteins. Therefore, the failure of a single
regulator may have almost no effect on the cell cycle, especially if more than one
mechanism controls the same event. Conversely, the effect of a deficient or non-
functioning regulator can be wide-ranging and possibly fatal to the cell if multiple
processes are affected.

1. Positive Regulation of the Cell Cycle

Two groups of proteins, called cyclins and cyclin-dependent kinases (Cdks),
are responsible for the progress of the cell through the various checkpoints. The
levels of the four cyclin proteins fluctuate throughout the cell cycle in a predictable
pattern. Increases in the concentration of cyclin proteins are triggered by both
external and internal signals. After the cell moves to the next stage of the cell cycle,
the cyclins that were active in the previous stage are degraded.
 Figure 3 Cyclin Concentrations at Checkpoints: The concentrations of cyclin
proteins change throughout the cell cycle. There is a direct correlation between
cyclin accumulation and the three major cell cycle checkpoints. Also, note the sharp
decline of cyclin levels following each checkpoint (the transition between phases of
the cell cycle) as cyclin is degraded by cytoplasmic enzymes.
Cyclins regulate the cell cycle only when they are tightly bound to Cdks. To be
fully active, the Cdk/cyclin complex must also be phosphorylated in specific
locations. Like all kinases, Cdks are enzymes (kinases) that phosphorylate other
proteins. Phosphorylation activates the protein by changing its shape. The proteins
phosphorylated by Cdks are involved in advancing the cell to the next phase.. The
levels of Cdk proteins are relatively stable throughout the cell cycle; however, the
concentrations of cyclin fluctuate and determine when Cdk/cyclin complexes form.
The different cyclins and Cdks bind at specific points in the cell cycle and thus
regulate different checkpoints.

Figure 4 Activation of Cdks: Cyclin-dependent kinases (Cdks) are protein

kinases that, when fully activated, can phosphorylate and activate other proteins that
advance the cell cycle past a checkpoint. To become fully activated, a Cdk must bind
to a cyclin protein and then be phosphorylated by another kinase.
2. Negative Regulation of the Cell Cycle
The second group of cell cycle regulatory molecules are negative regulators.
Negative regulators halt the cell cycle. Remember that in positive regulation, active
molecules cause the cycle to progress.
The best understood negative regulatory molecules are retinoblastoma protein (Rb),
p53, and p21. Retinoblastoma proteins are a group of tumor-suppressor proteins
common in many cells. Much of what is known about cell cycle regulation comes
from research conducted with cells that have lost regulatory control. All three of
these regulatory proteins were discovered to be damaged or non-functional in cells
that had begun to replicate uncontrollably (became cancerous). In each case, the
main cause of the unchecked progress through the cell cycle was a faulty copy of the
regulatory protein.
Rb, p53, and p21 act primarily at the G1 checkpoint. p53 is a multi-functional
protein that has a major impact on the cell’s commitment to division; it acts when
there is damaged DNA in cells that are undergoing the preparatory processes during
G1. If damaged DNA is detected, p53 halts the cell cycle and recruits enzymes to
repair the DNA. If the DNA cannot be repaired, p53 can trigger apoptosis (cell
suicide) to prevent the duplication of damaged chromosomes. As p53 levels rise, the
production of p21 is triggered. p21 enforces the halt in the cycle dictated by p53 by
binding to and inhibiting the activity of the Cdk/cyclin complexes. As a cell is exposed
to more stress, higher levels of p53 and p21 accumulate, making it less likely that the
cell will move into the S phase.
Rb exerts its regulatory influence on other positive regulator proteins. Rb
monitors cell size. In the active, dephosphorylated state, Rb binds to proteins called
transcription factors, most commonly to E2F. Transcription factors “turn on” specific
genes, allowing the production of proteins encoded by that gene. When Rb is bound
to E2F, production of proteins necessary for the G1/S transition is blocked. As the
cell increases in size, Rb is slowly phosphorylated until it becomes inactivated. Rb
releases E2F, which can now turn on the gene that produces the transition protein
and this particular block is removed. For the cell to move past each of the
checkpoints, all positive regulators must be “turned on” and all negative regulators
must be “turned off.”

Figure 5 Function of the Rb Regulator Molecule: Rb halts the cell cycle by binding
E2F. Rb releases its hold on E2F in response to cell growth to advance the cell
cycle.

MITOSIS AND MEIOSIS

In eukaryotic cells, the nucleus divides before the cell itself divides. The
process in which the nucleus divides is called mitosis. Before mitosis occurs, a cell’s
DNA is replicated. This is necessary so that each daughter cell will have a complete
copy of the genetic material from the parent cell. How is the replicated DNA sorted
and separated so that each daughter cell gets a complete set of the genetic
material? To understand how this happens, you need to know more chromosomes.
Chromosomes
Chromosomes are coiled structures made of DNA and proteins.
Chromosomes are the form of the genetic material of a cell during cell division.
During other phases of the cell cycle, DNA is not coiled into chromosomes. Instead,
it exists as a grainy material called chromatin.
Chromatids and Centromere
DNA condenses and coils into the familiar X-shaped form of a chromosome,
shown in Figure below, only after it has replicated. Because DNA has already
replicated, each chromosome actually consists of two identical copies. The two
copies are called sister chromatids. They are attached to one another at a region
called the centromere.
Chromosome. After DNA replicates, it forms chromosomes like the one shown
here.

Chromosomes and Genes

The DNA of a chromosome is encoded with genetic instructions for making
proteins. These instructions are organized into units called genes. Most genes
contain the instructions for a single protein. There may be hundreds or even
thousands of genes on a single chromosome.
Human Chromosomes
Human cells normally have two sets of chromosomes, one set inherited from
each parent. There are 23 chromosomes in each set, for a total of 46 chromosomes
per cell. Each chromosome in one set is matched by a chromosome of the same
type in the other set, so there are actually 23 pairs of chromosomes per cell. Each
pair consists of chromosomes of the same size and shape that also contain the
same genes. The chromosomes in a pair are known as homologous
chromosomes.
Mitosis and Cytokinesis
During mitosis, when the nucleus divides, the two chromatids that make up
each chromosome separate from each other and move to opposite poles of the cell.
This is shown in Figure below.
 Mitosis is the phase of the eukaryotic cell cycle that occurs between DNA
replication and the formation of two daughter cells. What happens during mitosis?
NOTE: Prokaryotic cells reproduce through binary fission where the cell
copies its DNA and then splits into 2 new cells.
Mitosis actually occurs in four phases. The phases are called prophase,
metaphase, anaphase, and telophase. They are shown in Figure below and
described in greater detail in the following sections.

Mitosis in the Eukaryotic Cell Cycle. Mitosis is the multi-phase process in

which the nucleus of a eukaryotic cell divides.
1. PROPHASE
The first and longest phase of mitosis is prophase. During prophase,
chromatin condenses into chromosomes, and the nuclear envelope, or membrane,
breaks down. In animal cells, the centrioles near the nucleus begin to separate and
move to opposite poles of the cell. As the centrioles move, a spindle starts to form
between them. The spindle, shown in Figure A below, consists of fibers made of
microtubules and Figure B below, shows a picture of Prophase.
 Figure A Figure B
Spindle. The spindle starts to form during prophase of mitosis. Kinetochores
on the spindle attach to the centromeres of sister chromatids.

2. METAPHASE
During metaphase, spindle fibers attach to the centromere of each pair of
sister chromatids (see Figure below). The sister chromatids line up at the equator, or
center, of the cell. The spindle fibers ensure that sister chromatids will separate and
go to different daughter cells when the cell divides.

Figure A Figure B
Chromosomes, consisting of sister chromatids, line up at the equator or
middle of the cell during metaphase.

3. ANAPHASE
During anaphase, sister chromatids separate and the centromeres divide.
The sister chromatids are pulled apart by the shortening of the spindle fibers. This is
like reeling in a fish by shortening the fishing line. One sister chromatid moves to one
pole of the cell, and the other sister chromatid moves to the opposite pole. At the end
of anaphase, each pole of the cell has a complete set of chromosomes.

4. TELOPHASE
During telophase, the chromosomes begin to uncoil and form chromatin. This
prepares the genetic material for directing the metabolic activities of the new cells.
The spindle also breaks down, and new nuclear membranes form.

5. CYTOKINESIS
Cytokinesis is the final stage of cell division in eukaryotes as well as
prokaryotes. During cytokinesis, the cytoplasm splits in two and the cell divides.
Cytokinesis occurs somewhat differently in plant and animal cells, as shown
in Figure below. In animal cells, the plasma membrane of the parent cell pinches
inward along the cell’s equator until two daughter cells form. In plant cells, a cell
plate forms along the equator of the parent cell. Then, a new plasma membrane and
cell wall form along each side of the cell plate.
 Cytokinesis is the final stage of eukaryotic cell division. It occurs differently in
animal (left) and plant (right) cells.

Meiosis
Meiosis is a type of cell division in which the number of chromosomes is
reduced by half. It is a process that produces haploid gametes. It occurs only in
certain special cells of the organisms. During meiosis, homologous chromosomes
separate, and haploid cells form that have only one chromosome from each pair.
Two cell divisions occur during meiosis, and a total of four haploid cells are
produced. The two cell divisions are called meiosis I and meiosis II. The overall
process of meiosis is summarized in Figure below. It is also described in detail
below.

Overview of Meiosis. During meiosis, homologous chromosomes separate

and go to different daughter cells. This diagram shows just the nuclei of the cells.
Notice the exchange of genetic material that occurs prior to the first cell division.
PHASES:
Meiosis I begin after DNA replicates during interphase. In both meiosis I and
meiosis II, cells go through the same four phases as mitosis. However, there are
important differences between meiosis I and mitosis. The flowchart
in Figure below shows what happens in both meiosis I and II. You can follow the
changes in the flowchart as you read about them below.
 Phases of Meiosis. This flowchart of meiosis shows meiosis I in greater
detail than meiosis II. Meiosis I—but not meiosis II—differs somewhat from mitosis.
Compare meiosis I in this flowchart with the earlier figure featuring mitosis. How
does meiosis I differ from mitosis?

A. Meiosis I
1. Prophase I: The nuclear envelope begins to break down, and the
chromosomes condense. Centrioles start moving to opposite poles of the cell,
and a spindle begins to form. Importantly, homologous chromosomes pair up,
which is unique to prophase I. In prophase of mitosis and meiosis II,
homologous chromosomes do not form pairs in this way. During prophase I,
crossing-over occurs (see below).
2. Metaphase I: Spindle fibers attach to the paired homologous chromosomes.
The paired chromosomes line up along the equator of the cell. This occurs
only in metaphase I. In metaphase of mitosis and meiosis II, it is sister
chromatids that line up along the equator of the cell.

3. Anaphase I: Spindle fibers shorten, and the chromosomes of each

homologous pair start to separate from each other. One chromosome of each
pair moves toward one pole of the cell, and the other chromosome moves
toward the opposite pole.

4. Telophase I and Cytokinesis: The spindle breaks down, and new nuclear
membranes form. The cytoplasm of the cell divides, and two haploid daughter
cells result. The daughter cells each have a random assortment of
chromosomes, with one from each homologous pair. Both daughter cells go
on to meiosis II.
 B. Meiosis II
1. Prophase II: The nuclear envelope breaks down and the spindle begins to
form in each haploid daughter cell from meiosis I. The centrioles also start to
separate.

2. Metaphase II: Spindle fibers line up the sister chromatids of each

chromosome along the equator of the cell.

3. Anaphase II: Sister chromatids separate and move to opposite poles.

4. Telophase II and Cytokinesis: The spindle breaks down, and new nuclear
membranes form. The cytoplasm of each cell divides, and four haploid cells
result. Each cell has a unique combination of chromosomes.
 At the end of meiosis, four haploid cells have been produced, but the cells are not
yet gametes. The cells need to develop before they become mature gametes
capable of fertilization. The development of haploid cells into gametes is
called gametogenesis.