Cell Cycle and Signaling

› Introduction
› Phases of cell division
› Checkpoints
› Meiosis
› Mitosis
› Checkpoints and cell cycle regulation
› Significance of cell cycle
Contents

The cellular life cycle also called the cell cycle
it includes many processes necessary for successful
self-replication. Beyond carrying out the tasks of
routine metabolism, the cell must duplicate its
components most importantly, its genome so that it
can physically split into two complete daughter cells.
The cell must also pass through a series of
checkpoints that ensure conditions are favorable for
division.
Cell Cycle

The cell cycle consists of four distinct phases:
G1 (Gap1) phase
S phase (synthesis
G2 (Gap2) phase (collectively known as interphase)
and M phase (mitosis).
M (mitosis) phase is itself composed of two tightly coupled
processes: mitosis
in which the cell's chromosomes are divided between the two
daughter cells, and cytokinesis…
in which the cell's cytoplasm divides in half forming distinct cells.
Activation of each phase is dependent on the proper progression
and completion of the previous one.
Cells that have temporarily or reversibly stopped dividing are said
to have entered a state of quiescence called G0 phase…
Phases of cell division

G0 phase
The G0 phase is a period in the cell cycle in which cells exist in a
quiescent state. G0 phase is viewed as either an extended G1
phase, where the cell is neither dividing nor preparing to divide,
or a distinct quiescent stage that occurs outside of the cell cycle.
G0 is sometimes referred to as a "post-mitotic" state…
G1 phase
The first phase of interphase is G1 phase, from the end of the
previous Mitosis phase until the beginning of DNA replication is
called G1 (G indicating gap). It is also called the growth phase.
During this phase the biosynthetic activities of the cell, which had
been considerably slowed down during M phase, resume at a
high rate. This phase is marked by synthesis of various enzymes
that are required in S phase, mainly those needed for DNA
replication…

S phase
Initiation of DNA replication is indication of S phase; when it
is complete, all of the chromosomes have been replicated, at
this time each chromosome has two (sister) chromatids.
Thus, during this phase, the amount of DNA in the cell has
effectively doubled, though the ploidy of the cell remains the
same. Rates of RNA transcription and protein synthesis are
very low during this phase. An exception to this is production
of histone protein, which mostly occurs during the S phase.

G2 phase
After S phase or replication cell then enters the G2 phase,
which lasts until the cell enters mitosis. Again, significant
biosynthesis occurs during this phase, mainly involving the
production of microtubules, which are required during the
process of mitosis. Inhibition of protein synthesis during G2
phase prevents the cell from undergoing mitosis.

In order to move from one phase of its life cycle to the next, a cell
must pass through numerous checkpoints. At each checkpoint,
specialized proteins determine whether the necessary conditions
exist. If so, the cell is free to enter the next phase..
Each part of the cell cycle features its own unique checkpoints.
For example, during G1, the cell passes through a critical
checkpoint that ensures environmental conditions are favorable
for replication. If conditions are not favorable, the cell may enter a
resting state known as G0. Some cells remain in G0 for the entire
lifetime of the organism in which they reside. For instance, the
neurons and skeletal muscle cells of mammals are typically in
G0.
Checkout points

› Another important checkpoint takes place later in the cell
cycle, just before a cell moves from G2 to mitosis. Here, a
number of proteins scrutinize the cell's DNA, making sure it
is structurally intact and properly replicated. The cell may
pause at this point to allow time for DNA repair, if
necessary.
› Yet another critical cell cycle checkpoint takes place mid-
mitosis. This check determines whether the chromosomes
in the cell have properly attached to the spindle, or the
network of microtubules that will separate them during cell
division. This step decreases the possibility that the
resulting daughter cells will have unbalanced numbers of
chromosomes a condition called aneuploidy

› Process of cell cycle must be highly regulated so that each
daughter cell contains the complement of DNA found in
parent cell.
› There are different mechanisms to control the timing of
events in the context of different cell types.
› Most important discoveries about mechanisms that control
events of cell were elucidated using yeast
› Results have shown many important control genes are
present
Checkpoints and Cell Cycle Regulation

› Many cell cycle control genes in mammalian cells are also
called cell division cycle genes.
› Much of the control of the progression through the phases
of a cell cycle are exerted at check points.
CDC Genes
Two most critical genes that occur near the end of G1 prior to S-
phase entry and those near the end of G2 prior to mitosis

› Heart of timing control is the responsibility of a family of
protein kinases that are called CDKs
› Oscillating changes in the activity of CDKs leads to
oscillating changes in phosphorylation of various
intracellular proteins. After phosphorylation the cyclins CDK
complex is fully active.
› Which then effect changes in events of cell cycle.
Cyclin Dependent Kinase

› The cyclical activity of each CDK is controlled by a series
of proteins, the most important of which are cyclins.
› CDK are dependent upon their interaction with the cyclins
for activity unless they are tightly bound CDKs without
kinase activity, level of various CDKs remain fairly constant
throughout the cell cycle, their activities changes in concert
with the fluctuations of cyclins
Cyclins

Four different types of Cyclins are there

G1-Cyclins
They are not found in all eukaryotes but those where they are
synthesized they promote passage through a restriction point in
late G1 called Start.
G1/S-Cyclins
They bind to their cognate CDKs at the end of G1 and it is the
interaction that is required to commit the cell to the process of
DNA replication in S-Phase
S-Cyclins
They bind to their CDKs during S-phase and it is the interaction
that is required for the initiation of DNA synthesis.
M-Cyclins
They bind to their cognate CDKs and in so doing promote the
events of mitosis.

› CDKs are inactive unless bound to a cyclin, there is more
to activation process than just the interaction of two parts
of complex.
› When cyclins bind to CDKs they alter the conformation of
CDK resulting in exposure of a domain that is site for
phosphorylation by another kinase called CDK activating
Kinase.
› Proteins that bind to and inhibit cyclin-CDK complexes are
called CDK inhibitory proteins
› CKI-cyclin kinase inhibitor (Example P21)
Interaction of CDKs

› The cyclical degradation of cyclins is affected through the
action of several different ubiquitin ligase complexes they
are two important ubiquitin ligase complexes.
› One of them which function to control transit from G1 to S-
phase and the other is called anaphase promoting
complex.
Ubiquitin ligase complexes

› Controls the level of M-phase cyclins as well other
regulators of mitosis.
› Controls initiation of sister chromatids separation which
begins at metaphase-anaphase transition.
Anaphase promoting Complex

› Mitosis is a process where a single cell divides into two
identical daughter cells (cell division).
› During mitosis one cell? divides once to form two identical
cells.
› The major purpose of mitosis is for growth and to replace
worn out cells.
› If not corrected in time, mistakes made during mitosis can
result in changes in the DNA? that can potentially lead to
genetic disorders?.

› INTERPHASE
› PROPHASE
› PROMETAPHASE
› METAPHASE
› TELOPHASE
› CYTOKINESIS
phases

Interphase
› The DNA in the cell is copied in preparation for cell
division, this results in two identical full sets of
chromosomes?.
› Outside of the nucleus? are two centrosomes, each
containing a pair of centrioles, these structures are critical
for the process of cell division.
› During interphase, microtubules extend from these
centrosomes.

› In this stage the nuclear envelope breaks down .
› Some mitotic spindle fibers elongate from the
centrosomes and attach to kinetochores.
› Other spindle fibers elongate but instead of attaching to
chromosomes, overlap each other at the cell center. -
Prometaphase

› The chromosomes line up neatly end-to-end along the
centre (equator) of the cell.
› The centrioles are now at opposite poles of the cell with the
mitotic spindle fibres extending from them.
› The mitotic spindle fibres attach to each of the sister
chromatids
Metaphase

› The sister chromatids are then pulled apart by the mitotic
spindle which pulls one chromatid to one pole and the
other chromatid to the opposite pole.
Anaphase

› At each pole of the cell a full set of chromosomes gather
together.
› A membrane forms around each set of chromosomes to
create two new nuclei.
› The single cell then pinches in the middle to form two
separate daughter cells each containing a full set of
chromosomes within a nucleus. This process is known as
cytokinesis
Telophase & cytokinesis

› Meiosis is the form of eukaryotic cell division that produces
haploid sex cells or gametes (which contain a single copy
of each chromosome) from diploid cells (which contain two
copies of each chromosome).
› The process takes the form of one DNA replication
followed by two successive nuclear and cellular divisions
(Meiosis I and Meiosis II).
Meiosis

› Two successive nuclear divisions occur
› Meiosis I (Reduction)
› Meiosis II (Division).
› Meiosis produces 4 haploid cells.
› Mitosis produces 2 diploid cells.
Phases of Meiosis

› Prophase I has a unique event -- the pairing of homologous
chromosomes.
› Synapsis is the process of linking of the replicated homologous
chromosomes.
› The resulting chromosome is termed a tetrad, being composed of
two chromatids from each chromosome, forming a thick (4-strand)
structure.
› Crossing over may occur at this point.
› During crossing-over chromatids break and may be reattached to a
different homologous chromosome.
› crossing-over between homologous chromosomes produces
chromosomes with new associations of genes and alleles.
Prophase 1

Metaphase I
› Metaphase I is when tetrads line-up along the equator of
the spindle. Spindle fibers attach to the centromere region
of each homologous chromosome pair. Other metaphase
events as in mitosis

› Anaphase I is when the tetrads separate, and are drawn to
opposite poles by the spindle fibers. The centromeres in
Anaphase I remain intact.
Anaphase I

› Telophase I is similar to Telophase of mitosis, except that
only one set of (replicated) chromosomes is in each "cell".
Depending on species, new nuclear envelopes may or may
not form. Some animal cells may have division of the
centrioles during this phase.
Telophase I

› During Prophase II, nuclear envelopes (if they formed
during Telophase I) dissolve, and spindle fibers reform. All
else is as in Prophase of mitosis. Indeed Meiosis II is very
similar to mitosis
Prophase II

› Metaphase II is similar to mitosis, with spindles moving
chromosomes into equatorial area and attaching to the
opposite sides of the centromeres in the kinetochore region
Metaphase II

› During Anaphase II, the centromeres split and the former
chromatids (now chromosomes) are segregated into
opposite sides of the cell.
Anaphase II

› Telophase II is identical to Telophase of mitosis.
Cytokinesis separates the cells.
Telophase II

› The hereditary material is equally distributed in the daughter
cells and the genetic information remains unchanged generation
after generation.
› Mitosis results in an increase in size and growth of an organism.
› Mitosis gives rise to many cells which differentiate to form
tissues and organs of the organism
› Regeneration, healing of wounds and replacement of older cells
all are the gifts of mitosis
› Organism requires, managed, controlled, and properly organized
process of mitosis if not so it will result in malfunction,
unwanted tumors and lethal diseases like cancers.
Significance of mitosis

› Crossing over and random assortment of chromosomes are two
significant happenings of meiosis.
› During crossing over, parental chromosomes exchange segments
with each other which results in a large number of
recombination’s
› Meiosis allows for new combination of genes to occur in the
gametes(cells involved in sexual reproduction).
› Meiosis increases genetic diversity, continue evolution, and
maintain a species.
Significance of meiosis

› Deletion: Sometimes during mitosis the chromosomes can be
damaged. If the chromosome gets broken the fragments can be lost. If
this happens the genetic material they contain is deleted.
› Translocation: If the chromosome breaks, it can reattach to another
chromosome. Sometimes it reattaches to the wrong chromosome.
› Inversion: When the fragment gets reattached it gets attached to the
right chromosome but upside down. When this happen it incorrectes
codes for information.
› Non-disjunction: Failure of paired chromosomes to separate (to
disjoin) during cell division,one cell is given three copies (trisomy) of
a chromosome while the other gets only one (monosomy).
Nondisjunction causes errors in chromosome number.
Errors

› Patau syndrome
› Down syndrome
› Cri-du-chat syndrome
› Turner syndrome
› Klinefelter syndrome
Consequences

› Patau's syndrome have an extra copy of chromosome 13 in every
cell of their body. it is also called trisomy 13. It is the most severe
of all chromosomal abnormalities which result in severe physical
and mental impairment as well as developmental delay.
Patau's syndrome

› Down syndrome is a genetic condition. It occurs when a child is
born with 47 chromosomes instead of the usual 46. The extra
chromosome causes delay in brain development and physical
abnormalities. There symptoms are:
 loose muscles and joints
 a small mouth and small head shape that is flatter at the back
 lower than average birth weight short
 Small ears
Down syndrome

› The name of this syndrome is French for "cry of the cat,"
referring to the cry of children with this disorder. Cri-du-chat is
caused by a deletion on the short arm of chromosome 5.
› A deletion is caused by a break in the DNA molecule that makes
up a chromosome.
› People who have cri-du-chat have a small head an unusually
round face, a small chin, widely set eyes and folds of skin over
their eyes.
Cri-du-chat syndrome

› Turner syndrome (TS) is a medical disorder that affects about 1
in every 2,500 females. Most females are born with two X
chromosomes, but females with Turner syndrome are born with
only one X chromosome. These females are sterile.
Turner syndrome

› Mitosis is closely controlled by the genes inside every cell.
› Cancer is essentially a disease of mitosis - the normal
'checkpoints' regulating mitosis are ignored by the cancer cell.
Cancer starts with one normal cell changing into a cancerous
cell;this may be due to a mutation in the cell's DNA that affects
its growth.
› Mass of cancer cells is called a tumor. When a tumor spreads to
another part of the body it is said to be metastasized.
Cancer (uncontrolled cell division)