Unit IV

Cell cycle, Events in cell cycle

Interphase, Mitotic phase,stages of mitosis
Mitotic blockage, Stimulators of mitosis,
Significance of mitosis.
Dr. Manikandan Kathirvel M.Sc., Ph.D., (NET)
Assistant Professor,
Department of Life Sciences,
Kristu Jayanti College (Autonomous),
(Reaccredited with "A" Grade by NAAC)
Affiliated to Bengaluru North University,
K. Narayanapura, Kothanur (PO)
Bengaluru 560077
 • Cell cycle (cell division cycle) is an
Mitosis ordered sequence of events occurring in
a cell.
• Cell cycle results in cell growth and DNA
replication thereby forming two daughter
cells.
• It is an essential process for the
formation of a mature organism from
single-celled fertilized eggs.
• The process of cell cycle promotes
renewal and regeneration of hair, blood
cells, skin, and certain internal organs.

Stages of Cell Cycle

I = Interphase, M = Mitosis; inner ring: M =
Mitosis, G1 = Gap 1, G2 = Gap 2, S =
Synthesis; not in ring: G0 = Gap 0/Resting.

Cells in actively growing tissue go through a cycle of metabolic activity,

DNA replication, chromosome segregation and cell division known as the
cell cycle.
Different Stages of a Cell Cycle
1. The events occurring in the life of the cell constitute cell cycle.
2. There are two phases of cell cycle: Interphase and Mitotic phase.
3. The duration of cell varies from hours to years.
4. A typical human cell cycle has duration of 24-90 hours.

Mitosis, the process of chromosome

condensation and separation into new
daughter nuclei,
Interphase: In this phase, the cell grows and produces a copy of the genetic
material (DNA).
1. It is the longest phase in a cell. Out of 90 hours, the interphase lasts for 89 hours.

2. It is the resting phase of the cell. It is the longest phase.

3. The nucleus is enlarged and intact and nuclear membrane is also intact of
nucleolus.

4. There is no cell division occurs in this phase. This stage prepares the cell for cell
division.
5. The metabolic activity is high in this phase.

6. The mRNA and rRNA are synthesized during this phase.

7. The chromosomes duplicates into 2 chromatids.

8. The centriole duplicates into 2, to form the centriole microtubule and

microfilaments start arising and this microtubules form asters.
9. Interphase can be further subdivided into three distinct phases: G1 phase, S
phase (synthesis), G2 phase.
G0 –phase:
• Resting phase of cell.
• Every phase will be successfully
activated on proper progression and
completion of the previous phases.
• However, if a cell is temporarily
stopped progressing or somehow
stopped dividing then the cell enter into
another state termed as G0 phase,
also called a “state of quiescence.”

•Gap 0 (G0) Phase: At times the cell will leave the cycle and temporarily stop
dividing. This is called a resting period. It can be for a short time or long
more permanent period.
•For example neurons after reaching the end stage of development stop
dividing and enter into a more permanent resting phase.
Sub-phases of Interphase
G1 phase:
1. Stands for gap phase.
2. It is the first growth period phase.
3. It is the longest phase.
4. The cell may last for years at this phase.
5. Daughter cell grows and increases in size.
6. The stage last for 25-50% of total interphase and proteins.
7. During this phase mRNA, rRNA and tRNA are synthesized in this phase.

•Gap 1 (G1) Phase: It is also termed as the first gap phase. In this phase, the
cell starts growing and enlarges physically. It forms the copy of organelles,
produces all the necessary molecular building blocks such as RNA and also
synthesizes proteins that are essential in later stages.
•During this phase, the cell is metabolically active and continues to grow without
replicating its DNA
•At this point, a control mechanism is activated to ensure proper DNA synthesis.
The control mechanism is termed as the G1 checkpoint.
 S-phase:
 S stands for synthesis phase.
 During this phase DNA synthesis
occurs.
 The DNA molecule duplicates.
 It last for 35-40% of interphase.

•S Phase: In this phase, a cell produces a complete copy of DNA in the

nucleus to produce two similar daughter cells. DNA replication begins in the
S phase or the synthesis phase. The microtubule-organizing structure
(centrosome) is also copied in this phase. The centrosome is the structure
that helps in dividing the DNA during M phase.
 G2 phase:
1. It is gap period between S phase and
mitotic phase of the cell cycle.
2. The nucleus increases in volume
increases in metabolic activity.
3. Transcription and translation of
missionary needed for cell division.
4. G2 phase is followed by Mitotic phase.

•Gap 2 (G2) phase: In G2 phase the cell grows further, produce proteins and
organelles and starts rearranging the constituents of the cell for mitosis phase.
•During this phase, the RNA, proteins, other macromolecules required for
multiplication of cell organelles, spindle formation, and cell growth are produced
as the cell prepares to go into the mitotic phase.
• At the end of the G2 phase, another checkpoint is activated called as G2
Checkpoint. G2 Checkpoint ensures everything is ready for division and M
phase. The G2 phase ends when the mitosis process begins.
2. Mitotic phase or M phase:
This is the division phase. M stands for mitosis.
During this phase the cell divides. This phase
has a short duration.

A typical human cell cycle has duration of 24-90

hours.
The M phase has the duration of 45 min to 1
hour and two phases:

A) Karyokinesis refers to the division of

Nucleus into two daughter nuclei. The cell’s
“nuclear DNA” is condensed into
chromosomes. These visible chromosomes
are pulled apart with the help of mitotic
spindles (the special structures formed from
microtubules). Karyokinesis has four sub
stages, namely prophase, metaphase,
anaphase and telophase.

B) Cytokinesis refers to the division of the

cytoplasm resulting in two daughter cells. In this
phase, the cytoplasm of the cell is divided into
two daughter cells.
Duration of the Cell Cycle

o The cell cycle duration will vary in different types of cells.

o The G1 phase will continue for approximately 11 hours,

o S phase will continue for 8 hours,

o G2 phase for nearly 4 hours and

o the M phase for nearly one hour in a rapidly dividing human cell with cell
cycle duration of 24 hours.

o Some cells may divide faster than human cells whereas some cells may
take more time to complete an entire cell cycle.

o For example “budding yeast” will complete the entire cell cycle (4 stages of
the cell cycle) in about 90 minutes.
Karyokinesis
Prophase
1. It is the first stage of mitosis.
2. Cell becomes spheroid and viscous
3. Nuclear membrane disintegrates
and disappears into a cytoplasm.
4. The chromosomes become
shortened and thickened.
5. Each chromosome is formed of two
chromatids. The two chromatids of a
chromosome are connected by a
centromere.
6. The nucleolus starts to disappear.
Metaphase
1. The chromosomes lie at
equatorial plane.
2. Fibres of spindle attach with
centromere of each
chromosome and are known as
chromosomal fibres.
3. The fibres which occurs in
between the chromosomes are
called interzonal fibres .
4. The centromere of each
chromosome divides into two.
Anaphase
1. The chromatids of each
chromosomes are separated and
move towards the opposite poles
forming daughter chromosomes.

2. The daughter chromosomes

achieved by the contraction of
centrosomal givers and the
stretching of the interzonal
fibres.
Telophase
1. The chromosome with their
centromeres at the poles begins to
uncoil and lengthens. They
aggregate together to form a mass
at the poles.
2. The nucleolus begins to reappear.
3. New nuclear membrane develops
around the chromosomes.
4. Two daughter nucleus are formed.
B) Cytokinesis:
• The division of the cytoplasm into
two daughter cells is called
Cytokinesis.

• The division starts as a

constriction. This constriction
depends and thus daughter cells
are formed from a single parent
cell.

• A unit membrane develops

between the two cells. This plane
of division of cytoplasm is
perpendicular to the spindle.
In cytokinesis, the cytoplasm of the cell is split in two, making two new cells.
Cytokinesis usually begins just as mitosis is ending, with a little overlap.

Importantly, cytokinesis takes place differently in animal and plant cells.

•In animals, cell division occurs

when a band of cytoskeletal fibers
called the contractile
ring contracts inward and pinches
the cell in two, a process called
contractile cytokinesis. The
indentation produced as the ring
contracts inward is called
the cleavage furrow. Animal cells
can be pinched in two because
they’re relatively soft and
squishy.

•Plant cells are much stiffer than

animal cells; they’re surrounded by
a rigid cell wall and have high
internal pressure. Because of this,
plant cells divide in two by
building a new structure down the
middle of the cell. This structure,
known as the cell plate, is made up
of plasma membrane and cell wall
components delivered in vesicles,
and it partitions the cell in two.
Q: Which is the longest phase of the cell cycle?
1.G2
2.G1
3.S
4.G0

Sol: The correct answer is option “B”. G1 phase is usually the longest phase of
cell cycle. G1 phase is the first gap phase where the cell is preparing for the
other stages of cell cycle. Moreover, G1 phase follows the mitosis cell division. It
is the time for the newly formed cells to grow before the DNA replication. So, the
G1 phase is the longest. G1 phase can vary in the different type of cells. It can
last for minutes such as prokaryotic cells, hours such as yeast or sometimes for
years such as liver cells.
Mitotic blockage, or the interruption of cell division during mitosis, can occur due to
various factors:

1. Anti-Microtubule Drugs:
These drugs interfere with microtubules, which are essential for spindle formation and
chromosome segregation during mitosis. Such interference leads to mitotic arrest.
Paclitaxel (Taxol). Paclitaxel stabilizes microtubules, preventing their depolymerization. This
inhibits the normal dynamic rearrangement of microtubules required for proper chromosome
segregation during mitosis.
Vincristine/Vinblastine:Mechanism: These vinca alkaloids disrupt microtubule assembly by
binding to tubulin, preventing the formation of the mitotic spindle.
2. DNA Damage-Induced Mitotic Block:
Cells have checkpoints in the cell cycle to detect and respond to DNA damage. If DNA
damage occurs, the cell can block progression into mitosis or arrest mitosis if the damage is
detected at this stage.
• Radiation-Induced DNA Damage
• Chemotherapy (e.g., Doxorubicin, Cisplatin)
3. Targeting Cell Cycle Regulatory Proteins:
Inhibition of proteins that regulate mitosis can also lead to mitotic blockage.
Cdc25 Phosphatase Inhibitors:
Cdc25 is a phosphatase that activates cyclin-dependent kinases (CDKs) required for entry into
mitosis. Inhibiting Cdc25 prevents the activation of CDK1/cyclin B, necessary for mitotic entry.
4. Nutrient Deprivation or Cellular Stress:
Stress conditions, such as nutrient deprivation such as Amino Acid Starvation, hypoxia, or
oxidative stress, can trigger cell cycle arrest to prevent mitotic progression in unfavorable
conditions.
5. Aneuploidy-Causing Agents:
These agents such as Nocodazole increase the likelihood of chromosome
missegregation, causing mitotic checkpoint activation.
Nocodazole disrupts microtubules, preventing the proper attachment of chromosomes
to the mitotic spindle.
Stimulation of cell division

The stimulation of cell division during mitosis (in somatic cells) is a highly regulated
process that ensures proper DNA replication and segregation into two daughter cells.
The cell division cycle, leading to mitosis, is divided into several phases: G1, S, G2,
and M (mitosis), with multiple checkpoints to ensure the fidelity of division. Here's a
detailed breakdown of the key processes involved in the stimulation of cell division
specifically during mitosis:

1. Activation of Cyclins and CDKs

•The Cyclin-CDK complex is essential for driving the cell through the phases of the
cell cycle, especially into mitosis.
•Cyclin B binds to CDK1 (Cyclin-dependent kinase 1) to form the Maturation
Promoting Factor (MPF). This complex is crucial for the cell to enter mitosis (M
phase) from the G2 phase.
•MPF phosphorylates several target proteins that promote:
• Chromosome condensation (via histone phosphorylation).
• Nuclear envelope breakdown.
• Spindle assembly.
•The activity of this complex is tightly regulated by phosphorylation and
dephosphorylation events.
Cyclins and Cyclin-Dependent Kinases (CDKs)
•Cyclins and CDKs are essential in regulating the cell cycle. Cyclins activate CDKs,
which then phosphorylate target proteins to drive the cell through different phases of
the cell cycle.
•Specific cyclins control each stage of the cycle:
• Cyclin D/CDK4 or CDK6 controls the G1/S transition.
• Cyclin E/CDK2 promotes entry into the S phase (DNA replication).
• Cyclin B/CDK1 drives the cell into mitosis (M phase).

Entry into Mitosis (M Phase)

•The cell enters mitosis in response to the activation of the Cyclin B/CDK1 complex.
•Mitotic kinases (such as Aurora kinases and Polo-like kinases) help ensure that
proper spindle assembly, chromosome segregation, and cytokinesis take place.

2. Growth Factors
•Growth factors are proteins or hormones that bind to receptors on the cell surface
and stimulate cells to enter the cell cycle. They activate signaling cascades that
promote the transition from the G0 or G1 phase to the S phase.
•Examples:
• Epidermal Growth Factor (EGF)
• Platelet-Derived Growth Factor (PDGF)
• Fibroblast Growth Factor (FGF)
3. Nutritional Status and Energy Sensing
•Cells require a sufficient supply of nutrients and energy to divide. The AMPK and
mTOR pathways play crucial roles in sensing energy levels.
•The mTOR pathway promotes protein synthesis and cell growth, thus stimulating
cell division when conditions are favorable.
•The mTOR (mechanistic target of rapamycin) pathway senses nutrient and
energy status. When conditions are favorable (i.e., sufficient nutrients, energy,
and growth factors), mTOR promotes protein synthesis and cell growth,
ensuring that the cell has the necessary resources to complete mitosis.
•Activation of the mTOR pathway further stimulates mitosis by promoting the
production of proteins required for spindle assembly and chromosome
segregation.

4. Anaphase Promoting Complex (APC/C)

•The Anaphase Promoting Complex/Cyclosome (APC/C) is a ubiquitin ligase
that triggers the transition from metaphase to anaphase by marking specific
proteins for degradation.
•One of its targets is securin, which inhibits the enzyme separase. Upon securin
degradation, separase is activated, leading to the cleavage of cohesin proteins
that hold sister chromatids together, allowing them to separate and move to
opposite poles of the cell.
•APC/C also targets cyclin B for degradation, leading to the inactivation of CDK1,
which is necessary for the exit from mitosis and the completion of cytokinesis.
5. Mitotic Checkpoints
•The Spindle Assembly Checkpoint (SAC) ensures that all chromosomes are
correctly attached to the spindle microtubules before proceeding to anaphase.
•This checkpoint prevents the premature separation of sister chromatids and
ensures that mitosis only proceeds when the conditions are optimal for correct
chromosome segregation.
•Proteins like BubR1, Mad2, and Cdc20 are key players in regulating this
checkpoint.

6. Cytokinesis
•Following mitosis, cytokinesis divides the cytoplasm and organelles between the
two daughter cells. The process is mediated by a contractile ring composed of
actin and myosin filaments that constrict the cell membrane to form two separate
cells.
•Cytokinesis is regulated by the Rho family of GTPases, which control the
organization of the actin cytoskeleton during this process.
Significance of mitosis:
Mitosis is an essential biological process with several critical functions for the
growth, maintenance, and survival of multicellular organisms. Its significance
spans various biological contexts, from normal tissue growth to healing and even
its implications in disease processes such as cancer.

1.Mitosis helps maintain the number of chromosomes during cell division.

Mitosis ensures that each daughter cell receives an identical set of chromosomes.
This is crucial for maintaining the diploid chromosome number (2n) in somatic
cells. Errors in mitosis can lead to an abnormal number of chromosomes
(aneuploidy), which may result in developmental disorders or diseases like
cancer.
1.This process is important for the growth and development of organisms
•Mitosis is the primary mechanism by which multicellular organisms grow. It
allows a single fertilized egg (zygote) to develop into a fully formed organism by
producing billions of cells through successive divisions.
•It ensures that each daughter cell receives an identical set of genetic information,
maintaining consistency across the body's tissues.

3. It helps repair damaged tissues. Mitosis plays a crucial role in wound

healing and tissue regeneration.

4. It helps the cell to maintain proper size

5. Unregulated Mitosis and Cancer: While mitosis is usually a well-regulated
process, when the regulatory mechanisms fail, uncontrolled cell division can
occur, leading to tumor formation and cancer. Cancer cells bypass normal cell
cycle controls and divide rapidly through mitosis. Understanding mitosis is key in
cancer research for developing therapies that target cell division.

6. Maintenance of Multicellular Organisms

Homeostasis: Mitosis plays a critical role in maintaining tissue homeostasis by
balancing cell death (apoptosis) and cell division. For example, in tissues like the
intestines, where cells are regularly lost, mitosis ensures a constant supply of
new cells to maintain normal function.
7. Replacement of Senescent Cells
Over time, cells undergo senescence and lose their ability to divide. Mitosis
ensures that new, healthy cells replace these senescent cells, thus maintaining
the integrity of tissues and organs.
8. Role in Immune Response
During an immune response, certain white blood cells like T cells and B cells
proliferate rapidly through mitosis. This clonal expansion is necessary for
mounting a strong defense against pathogens like bacteria and viruses.
Summary of Mitosis Significance:
•Growth: Allows organisms to increase in size and complexity.
•Tissue Repair: Replaces damaged or dead cells, facilitating healing.
•Genetic Stability: Ensures daughter cells have identical genetic
information.
•Asexual Reproduction: Enables single-celled organisms and some
plants to reproduce without genetic variation.
•Homeostasis: Maintains cellular equilibrium in tissues.
•Disease Implications: Abnormal mitosis can lead to cancer, making it a
key target for therapies.