Mitosis

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The Cell Cycle

 The cell cycle is the sequence of events that take place to


enable DNA replication and cell division. It can be divided
into two phases: interphase and mitosis.
 Interphase is further divided into the G1 (gap 1), S
(synthesis), and G2 (gap 2) phases, which prepare the cell
for division.
 In mitosis, the single cell is dividing into two identical
Overview daughter cells.
 The cell cycle is subject to strict controls that prevent cells
with damaged or faulty DNA from further dividing and
passing on defects to daughter cells.
 Controlled cell death (apoptosis) is initiated if
the DNA damage is irreparable. Disorders of these
regulatory mechanisms play an important role in
carcinogenesis.
• Definition: the sequence of events
through which cell growth,
DNA replication, and cell division occur
• Characteristics
Cell Cycle • The cell involves two phases: interphase
Phases and mitosis.
• Interphase further involves the G1 phase
(gap 1), S phase (synthesis), and G2 phase
(gap 2), which prepare the cell for division.
Interphase is further divided into the G1 (gap 1), S
(synthesis), and G2 (gap 2) phases, which prepare the
cell for division.

In the G1 phase, proteins and cell organelles are


synthesized.

DNA is replicated in the S phase.

In the G2phase, DNA replication errors are repaired.

Interphase is followed by mitosis (M) or cell division.


There are various checkpoints within the cell cycle
that ensure the cell is ready to enter the next phase
(G1, G2, and M checkpoints).

Only proliferating cells pass through the cell cycle.


Most mature tissue cells are in a resting phase,
the G0 phase. These cells are differentiated, with each
performing a specific function. Mature differentiated
cells do not divide.
Homologous chromosomes
before and after replication
Somatic cells contain 23 pairs
of homologous chromosomes
(example on left). After
replication, each chromosome
consists of a pair of identical
sister chromatids connected at
the centromere (right).
What is Chromatin?
Complex of DNA and its associated proteins(both histones and non-
histones) structured as repetitive units (nucleosome)
What is Heterochromatin?
•Contains inactive DNA because the highly condensed, steric
conformation does not allow transcription
•Darker on electron microscopy (EM)
•DNA is highly methylated and deacetylated

What is Euchromatin?
•Contains active DNA because the less condensed steric conformation makes
DNA accessible for transcription
•Lighter on EM

What is Chromosome?
A denser packaging of chromatin that only becomes visible under the microscope during cell
division (especially in metaphase)
Chromosomes
•Chromosome: a structure found in the nucleus of eukaryotic cells that
contains nucleic acids and associated proteins (e.g., nucleosomes)
• Contains part or all of the genetic information for a given organism
• Each human cell contains 23 pairs of homologous
chromosomes (corresponding in structure and genetic information,
i.e., 23 chromosomes are inherited from each parent).
• Germ cells only carry one-half of a somatic cell's chromosomes.
• Can be visualized under a microscope during metaphase
•Chromatid: one of the two identical strands of a replicated chromosome
•Sister chromatids: two identical chromatids joined at the centromere (i.e., the duplicated
chromosome)
•Centromere: a condensed region of chromosomes where sister chromatids join
• Divides the chromatids into a short p arm and a long q arm
• Mediates attachment of the chromosome to the meiotic or mitotic spindle.
• Depending on the centromere position, a chromosome can be:
• Metacentric: The p and q arms are of approximately identical length.
• Submetacentric: The p arm is short and the q arm is long.
• Acrocentric: The p arm is much shorter than the q arm.
•Kinetochore: a protein complex found at the centromere that allows for the attachment of
mitotic spindle microtubules during mitosis
•Telomere
• Repetitive, noncoding DNA sequence at the ends of each chromosome, which prevents the
loss of coding DNA sequences during DNA replication
• Telomere shortening occurs after each cell division, which can reduce a cell's life span.
Interphase
•Definition: the interval between cell divisions in which the cell prepares for the next division
•Duration: variable
•3 phases of interphase (excluding the G0 phase)

• G1 phase (several hours to months) – Cell getting


ready for DNA replication
• Synthesis of RNA, proteins, and cell organelles
• Occurs after mitosis
• There is one chromatid present per chromosome.
• The cell grows during this phase
• Nucleotide excision repair takes place. Which genetic disorder when nucleotide excision repair
is defective?
• G1 checkpoint before entering S phase
• S phase (∼ 8 h)
• DNA replication results in two sister chromatids per chromosome.

• Synthesis of proteins required for DNA packaging (especially


histones)

• Most mismatch repair takes place during the S phase. – Which


genetic disorder?

• Once the S phase is initiated, the cell cycle must be completed.


G0 phase (resting phase)
LABILE CELLS - Some cells don’t go
•Definition: a resting phase which a cell enters into G0 PHASE because they need
after exiting the cell cycle from the G1 phase to be keep proliferating–
SKIN CELL
•Duration: variable GI TRACT CELLS
•Characteristics HEMATOPOETIC CELLS
• Cells that enter the G0 phase are
differentiated, have specific functions, and STABLE CELLS – proliferate when
are no longer undergoing cell division. needed because of some
stimuli/injury
• Most mature tissue cells are in the G0 phase. Kidney cells, Pancreatic cells, Liver
• Certain cell types reenter the G1 phase after cells, Alveolar Cells.
the G0 phase when exposed to certain
PERMANENT CELLS
stimuli (e.g., hepatocyte proliferation after Do not multiply again, Once fully
hepatectomy). differentiated they stay in G0
phase Neurons, Muscle cells:
myocardial cells, skeletal muscle
cells.
• G2 phase (∼ 2–5 h)
• Further synthesis of proteins required for
mitosis
• Repair of DNA replication errors
• G2 checkpoint before entering mitosis
•Definition: the process of cell division from the distribution of DNA to
the budding of a cellular body
•Duration: ∼1 h (shortest phase of the cell cycle)
Mitosis
•Definition: the final phase of the cell cycle, following the replication
of DNA
•5 phases of mitosis
• Prophase
• Chromosome condensation
• Centrosome separation: The centrosome is the point of origin of the
mitotic spindle. It consists of two centrioles and a surrounding matrix, from
which the microtubules emerge.
• Formation of the mitotic spindle
• Prometaphase
• Degradation of the nuclear membrane into small vesicles and storage of
intercellular vesicle
• Completion of the mitotic spindle formation
• Metaphase: maximal condensation of the chromosomes, which are aligned
Mitosis along the equatorial plane of the cell
• Anaphase
• Separation of sister chromatids due to cohesion dissolution at the
centromere by the enzyme separase
• Cell elongation
• Telophase
• Decondensation of the chromosomes
• Disintegration of the mitotic spindle
• Formation of a new nuclear membrane
• Cell bodies division at the equatorial plane
• Ribosomal RNA (rRNA) synthesis
• Chromosome condensation (by phosphorylation
of histones)
• Centrosome separation: The centrosome is the
point of origin of the mitotic spindle.
• Nuclear membrane starts dissolving – by
Prophase phosphorylating laminin proteins in nuclear
membrane
• It consists of two centrioles and a surrounding
matrix, from which the microtubules emerge.
• Formation of the mitotic spindle
Centrosomes are organelles
that serve as the main
microtubule organizing
centers for animal cells.
Microtubules are one type of
filament protein in the
cytoskeleton. Microtubule
networks grow from the
centrosomes and reach
every inch of the cells.
Microtubules can serve as a
cell’s skeleton to change the
cell shape.
During cell division,
centrosomes duplicate and
move toward the opposite poles
of dividing cells to help the
precise separation of
chromosomes (otherwise, the
wrong chromosome numbers
can cause cancer). All of these
functions rely on the
coordination of centrosomes!
In a centrosome, two centrioles are surrounded by a dense
protein mass, termed the pericentriolar material (PCM),
which is a complex of proteins that help additional
Centrosomes are microtubules to form. The PCM contains proteins that allow
sometimes referred to as the centrosomes to start and stop the formation of
the “MTOC,” or microtubule filaments. This allows centrosomes to control
“microtubule organizing the formation of mitotic spindle fibers and other structures
center” of the cell. that play important roles in the cells.
Centrosomes are made
of
two centrioles arranged
at right angles to each
other. Centrioles are
barrel-shaped clusters of
microtubule cores. Each
centriole is based on a
nine-triplet microtubule
assembled in a cartwheel
structure with several
associate proteins.
Proper functioning of the mitotic spindle is a
prerequisite for chromosome transportation.
Inhibition with spindle poisons leads to arrest of
mitosis and cessation of cell division. Spindle
poisons include colchicine, which inhibits
microtubule polymerization, as well as
vinca alkaloids and taxanes.
Prophase of mitosis
Microscopic image of 3D Structured
Illumination Microscopy (3D-SIM-
microscopy) of the nuclei of two
mouse cells
The highly condensed chromosomes
are red, the nuclear envelope is blue,
and the microtubules are green. The
mitotic spindle can be seen in the
upper right and lower left part of the
image.
Centrioles
Centrosomes are organelles present in the
cytosol that nucleate microtubules of a cell
during mitosis. They are essential for
chromosome separation in the anaphase of
mitosis. Two centrioles are present in the center
of the centrosome and are perpendicular to one
another. They are made up of nine microtubule
triplets, which are arranged as a short cylinder
(9x3+0 structure), resembling the basal bodies
of kinocilia.
Late telophase (mitosis)
Immunofluorescent staining of two
daughter cells in late telophase
(mouse cells): chromosome
condensation (DAPI staining; blue),
dividing cell along the equatorial
plane (actin cytoskeleton in phalloidin
staining; green), and disintegration of
the spindle apparatus (anti-tubulin
staining; orange)
Cytokinesis
•Definition: the division of a cell's cytoplasm
into two new cell bodies
•Characteristics
• Usually begins at the end of anaphase
• Cytoplasm and cell organelles are
distributed between the two new cells.
• Each of the new cells contains one copy
of the sister chromatids.
Basic principles of cell cycle regulation
•S phase initiation
• Certain growth factors (e.g., insulin, EGF, EPO, PDGF) stimulate the cell to go
from G1 phase into the S phase by binding to tyrosine kinase receptors.
• Epidermal growth factor inhibitors (EGFRi) such as erlotinib (used in
nonsmall cell lung cancer) and cetuximab (used in colorectal cancer and
head/neck cancer) block the progression of a cell from the G1 phase to the
S phase.
•Cyclin-dependent kinase (CDK)
• A type of inactive kinase that must be activated to enable the transition from one
phase of the cell cycle to the next
• Present throughout the entire cell cycle
• Activated via binding of cyclins to form cyclin-CDK complexes
• Inhibited by cyclin-dependent kinase inhibitor proteins (CDKIs) if any errors in
the genome are detected
•Cyclins
• A group of regulatory proteins that activate CDKs and, therefore, play an important role in controlling the cell cycle
• There are specific cyclins for specific phases of the cell cycle.
• Cyclin A: a protein that regulates cell cycle transition by binding to cyclin-dependent kinases (CDKs) 1 and 2.
• The transcription of cyclin A begins at the G1 restriction point and peaks in the middle of the S phase.
• The cyclin A-CDK2 complex allows the transition from the G1 to the S phase, and the cyclin A-CDK1
complex allows the transition from the S to the G2 phase.
• Cyclin B: a component of mitosis promoting factor, a cyclin-CDK complex that regulates the G2 checkpoint of
the cell cycle
• Cyclin C
• A protein that regulates cell cycle transition by binding to cyclin-dependent kinases (CDKs) 3 and 8
• The cyclin C-CDK3 complex allows the transition from the G0 to the G1 phase, and the cyclin C-CDK8
complex regulates gene transcription by phosphorylating transcription factors and RNA polymerase II.
• Cyclin D
• A protein that regulates the transition from G1 to S phase in the cell cycle via activation of
cyclin-dependent protein kinases
• Forms a complex with CDK4, which initiates DNA replication by inactivating retinoblastoma protein
• Cyclin E: a protein that regulates the transition from the G1 to the S phase of the cell cycle by binding to
cyclin-dependent kinase 2 (CDK2) and activating it
•Tumor suppressors
• A group of proteins that arrest and modulate (e.g., repair or induce
apoptosis) the cell cycle of cells with an abnormal genome
• DNA mutations can lead to defective tumor suppressor genes allowing
cells to divide uncontrollably.
• Examples
• BRCA-1/BRCA-2 (DNA repair proteins): defect associated with
breast cancer
• NF1: defect associated with neurofibromatosis type 1
• p53: defect associated with Li-Fraumeni syndrome
• APC: defect associated with familial adenomatous polyposis
• pRb: defect associated with retinoblastoma
•Cyclin-CDK complexes
• A type of protein complex with an enzymatic function
that phosphorylates other proteins to regulate the
progression of the cell cycle
• The physiological progression of the cell cycle depends on
the appropriate activation and deactivation of
cyclin-CDK complexes at specific checkpoints.
The p53 tumor suppressor prevents cells
with genetic errors from entering the S phase of
the cellcycle.

Mutations in tumor suppressor genes result in uncontrolled


proliferation. An important example is Li-Fraumeni syndrome,
resulting from a mutation in the p53 tumor suppressor gene.
Important checkpoints and transition points
•Definition: A cell cycle checkpoint is a specific point in time that marks the transition from
one cell cycle phase to another during which the current condition of a cell is revised (i.e., if all
requirements for the transition to the next phase are met)
• If DNA is faulty or damaged, the cell cycle can be stopped in order to repair the DNA.
• Apoptosis is initiated if the DNA damage is not repaired.
G1 checkpoint
•Definition: a cell division checkpoint during the G1 phase that restricts entry into the S phase
•Characteristics
• Controls the cell's nuclear-cytoplasmic ratio, sufficient nutrient levels, and DNA damage
• Growth signals lift the checkpoint.
• Cells that pass this checkpoint become committed to division.
• Dysfunction of this checkpoint (e.g., from loss of p53 function) leads to unregulated cell
division.
•Regulation
• Cyclin D/Cdk4 complex
• A regulatory protein complex that initiates DNA replication by inactivating pRb
• Cyclin D/CDK4 complex phosphorylates pRb → pRb inactivation → release of previously bound
transcription factor E2F → transcription of genes that are required for DNA replication
• p53 tumor suppressor
• A protein that inhibits DNA replication by activating pRb and initiates apoptosis of the cells with
irreparable DNA damage
• DNA damage → activation of protein kinases → phosphorylation of p53 → activation
of p21 → inhibition of Cdks → inhibition of Cdk-mediated phosphorylation of pRb → pRb
activation and binding of transcription factor E2F → cell arrest in the G1 phase (no entry into the
S phase)
• Activation of the p27 protein (a phosphoprotein that prevents cell cycle progression by inhibiting cyclin/
cyclin-dependent kinase complexes) leads to the same sequence of events.
• Present in every cell but undergoes continuous ubiquitylation and degradation
• Phosphorylated p53 can no longer be ubiquitinylated and degraded, leaving it free to act as a
transcription factor.
• Proapoptotic active proteins of the Bcl-2 family such as Bax and Bak
G2 checkpoint
•Definition: a cell division checkpoint during the G2 phase
•Characteristics
• Checks for DNA damage and completeness of DNA replication
• Initiates mitosis by phosphorylation of various proteins (e.g., histones)
• Also an important regulator for synchronized cell division of multiple cells
•Regulation: mitosis promoting factor (MPF), which is composed of Cdk1 and
cyclin B
M checkpoint (spindle checkpoint)
•Definition: a checkpoint between metaphase and anaphase in mitosis
•Characteristics: ensures correct alignment of the chromosomes and
sister chromatids at the equatorial planebefore the separation of sister chromatids
MEIOSIS
•Definition: germ cell maturation in which four daughter cells with a recombinant genome are produced from
one germ cell
•Process: Meiosis involves two major phases (referred to as meiosis I and meiosis II) occurring after
DNA replication during the S phase of interphase.
• Meiosis I (equatorial division)
• Synapsis (syndesis): the pairing of homologous chromosomes
• Genetic recombination: Individual chromosome segments are exchanged between the maternal and
paternal chromatids of homologous chromosomes (recombination) in a process known as
crossing over.
• Chromosome number reduction:
• A diploid set of chromosomes is divided in half when the homologous chromosomes separate
from one another.
• Disjunction of chromosomes occurs without centromere splitting generating 2 haploid
daughter cells, each with 23 chromosome pairs.
• Meiosis II (nuclear division):
• Generally corresponds to the phases of mitosis
• Sister chromatids of each chromosome from the haploid set separate from each other.
• Disjunction occurs with centromere splitting; each cell entering meiosis II produces 2
daughter cells, each with 23 chromosomes.
•Result
• Cell number: 1 mother cell → 4 daughter cells
• Set of chromosomes: diploid mother cell (2n) →
haploid daughter cell (1n)
• DNA content: 4 chromatids of the mother cell (4C)
→ 1 chromatid per daughter cell (1C)
• For sex-specific features, see
female reproductive organs and
male reproductive organs.
Comparative representation of mitosis
(i.e., cell division) and meiosis (i.e.,
germ cell production). With each
round, 2 diploid daughter cells or 4
haploid gametes are produced. During
meiosis, the process of crossing over
(exchange of blue and yellow
chromosomal segments) can be seen.
n: number of sets of chromosomes; c:
amount of DNA or number of
chromatids
During the course of meiosis, four gametes develop from one mother cell.
For the recombination of genetic material, two processes occur in meiosis I. The original mother and father
chromosomes are randomly distributed to the daughter cells. During prophase I, a crossing-over of the homologous
chromatids occurs (formation of chiasmata), resulting in an exchange of genetic material.
Germ cell development (gametogenesis)
Primordial germ cell development
•Occurs during the 4th week of embryonic development
•Primordial germ cells arise from the yolk sac and migrate to the developing
gonads of the urogenital folds.
•After meiosis, primordial germ cells mature to sex-specific gametes (oocytes
and spermatozoa).
Germline
•Definition: the cells that develop into mature germ cells (gametes), which pass
genetic material on to progeny
•Process: involves meiosis of primordial germ cells within the gonads
• Oogenesis (development and maturation of the ova): the production of an
oocyte with 2–3 polar bodies
• Spermatogenesis (sperm cell development): production of four functional
spermatids

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