Download TEXT The cell cycle, or cell-division cycle, is the series of events that

TEXT
The cell cycle, or cell-division cycle, is the series of
events that take place in a cell leading to its division and
duplication (replication). The cell cycle may also be
defined as
“An ordered cycle of complex events, resulting in cells
proceeding to cell division from a resting state.”
Fig 1:- Graphic Representations of Cell Cycle
The
cell
division
cycle
(Fig.1)
is
a
carefully
choreographed series of events that culminates in cell
division. The fundamental task of the cell cycle is to
faithfully replicate DNA and to equally distribute identical
chromosome copies to two daughter cells (Fig. 1-a).
Genetic
defects
affecting
the
cell
cycle
machinery
contribute to uncontrolled cell division, the hallmark of
cancer.
Fig. 1-a: Chromosome
The length of the cell cycle is important because it
determines how quickly an organism can multiply. For
single-celled organisms, this rate determines how quickly
the organism can produce new, independent organisms.
For higher-order species, the length of the cell cycle
determines how long it takes to replace damaged cells.
The duration of the cell cycle varies from organism to
organism and from cell to cell. Certain fly embryos sport
cell cycles that last only 8 minutes per cycle. Some
mammals take much longer than that--up to a year in
certain liver cells. Generally, however, for fast-dividing
mammalian cells, the length of the cycle is approximately
24 hours (Fig.2)
Fig. 2:- Duration of Cell Cycle
There are two major phases of cell cycle: Interphase
and Mitosis.
INTERPHASE
Interphase (Fig. 3) is the "holding" stage or the
stage between two successive cell divisions. It is the
phase of the cell cycle in which the cell spends the
majority of its time and acheived the majority of its
purposes, including preparation for cell division. In
preparation for cell division, it increases its size and
number of organelles, and makes a copy of its DNA.
Interphase is also considered to be the 'living' phase of
the cell, in which the cell obtains nutrients, grows, reads
its DNA, and conducts other "normal" cell functions. The
majority of eukaryotic cells spend most of their time in
interphase. Interphase does not describe a cell that is
merely resting, but is rather an active preparation for cell
division.
Fig. 3:- Cells in Interphase Stage
Under a microscope, interphase can be visually
recognized because the nuclear membrane is still intact,
the
chromatin
has
not
yet
condensed
and
the
chromosomes are not visible, though nucleolus may be
visible as an enlarged dark spot. The centrioles (Fig. 4.)
and spindle fibers are also not yet visible, though the
centrosome which contains and organizes them may be
visible near the nucleus.
The duration of time spent in interphase and in
each stage of interphase is variable and depends on both
the type of cell and the species of organism it belongs to.
Most cells of adult mammals spend about 20 hours in
interphase, this account for about 90% of the total time
involved in cell division (Mader, 2007).
Fig. 4:- Structure of Centriole
Stages of Interphase
There are four stages of interphase, each phase ends
when a cellular checkpoint (Fig. 5) checks the accuracy of
the stage's completion before proceeding to the next. The
stages of interphase are:
G0 - Rest phase,
G1 -1st gap phase where cells prepare to synthesize DNA
and undergo mass synthesis,
S - Cells synthesize DNA and double 2n to 4n,
G2 - 2nd gap phase where the cells prepare to divide.
Fig. 5:- Cell Cycle with various Checkpoints.
In cells without a nucleus (prokaryotes), the cell
cycle occurs via a process termed binary fission. In cells
with a nucleus (eukaryotes), the cell cycle can be divided
into Interphase and M phase.
Fig. 6:- DNA Replication
State
Quiescen
t/
senescen
t
Interpha
se
Phase
Gap 0
Gap 1
Abbrev
iation
Description
G0
A resting phase where the
cell has left the cycle and
has stopped dividing.
G1
Cells increase in size in
Gap 1. The G1 checkpoint
control mechanism ensures
that everything is ready for
DNA synthesis.
Synthesi
s
Gap 2
Cell
division
Mitosis
S
DNA replication occurs
during this phase (Fig. 6)
G2
During the gap between
DNA synthesis and mitosis,
the cell will continue to
grow. The G2 checkpoint
control mechanism ensures
that everything is ready to
enter the M (mitosis)
phase and divide.
M
Cell growth stops at this
stage and cellular energy is
focused on the orderly
division into two daughter
cells. A checkpoint in the
middle of mitosis
(Metaphase Checkpoint)
ensures that the cell is
ready to complete cell
division.
G0 (Gap) Phase of Cell Cycle
During G0 phase cells withdraw from the cell cycle,
are dormant, and do not grow or divide. This is a way for
multicellular organisms to control cell proliferation. The
time cells spend in G0, and the specific signals needed to
move the dormant cell back into the cell cycle, vary
greatly, depending on the type of cell. Cells can remain in
this phase for days, weeks, or even years. Most of the
cells in multicellular organisms, including humans, are
currently in this phase. For example, muscle and nerve
cells are permanently in a state of G0. Liver cells (Fig. 6a) also remain in this phase unless they are stimulated to
grow after an injury.
Fig. 6-a: Liver Cells
The term "post-mitotic" is sometimes used to refer
to both quiescent and senescent cells. No proliferative
cells in multicellular eukaryotes generally enter the
quiescent G0 state from G1, and may remain quiescent for
long periods of time, possibly indefinitely (as is often the
case for neurons). This is very common for cells that are
fully differentiated. Cellular senescence is a state that
occurs in response to DNA damage or degradation that
would make a cell's progeny nonviable; it is often a
biochemical alternative to the self-destruction of such a
damaged cell by apoptosis.
At a certain point in G1 phase the cell monitors
internal and external environments to determine if it
should go through the entire cell cycle and divide. If the
cell senses that there are not enough nutrients, such as
amino acids or growth factors for division, then it often
enters into G0 phase. During this time normal cellular
activities are drastically reduced. For example, protein
synthesis is inhibited by 50 to 80% and many proteins
are degraded. Enzymatic activity and RNA synthesis (Fig.
7) are also severely inhibited. Cells in G0 can quickly reenter G1 and progress through the cell cycle, if they
receive signals that nutrients are available for cell
division.
Additionally, some cells which do not divide often or
ever, enter a stage called G0 (Gap zero), which is either a
stage separate from interphase or an extended G1 phase,
which follows the restriction point, a cell cycle checkpoint
found at the end of G1.
Fig. 7:-Graphic Representation of RNA Synthesis
G1 (Gap1) Phase of Cell Cycle
The G1 phase is a period in the cell cycle during
interphase, after cytokinesis and before the S phase. For
many cells, this phase is the major period of cell growth
during its lifespan. During this stage, new organelles are
being synthesized, so the cell requires both structural
proteins and enzymes, resulting in great amount of
protein synthesis and a high metabolic rate in it. G1
consists of four sub phases:
i)
Competence (g1a)
ii)
Entry (g1b)
iii) Progression (g1c)
iv) Assembly (g1d)
These sub phases may be affected by limiting growth
factors, nutrient supply and additional inhibiting factors.
A rapidly dividing human cell which divides every 24
hours, spends 9 hours in G1 phase.
A cell may pause in the G1 phase before entering the S
phase, and enter a state of dormancy called the G0
phase. Most mammalian cells do this. In order to divide,
the cell re-enters the cycle in S phase.
Status of the Genome
The DNA in a G1 diploid eukaryotic cell is 2n,
meaning there are two sets of chromosomes present in
the cell. The genetic material exists as chromatin, and if
it were coiled into chromosomes, there would be no sister
chromatids. Haploid organisms, such as some yeasts,
(Fig 7-a)will be 1n and thus have only one copy of each
chromosome present.
Fig. 7-a: Yeast Cells
Restriction Point
There is a "restriction point" present at the end of G1
phase (Fig 5). This point is a series of safeguards to
ensure the DNA is intact and that the cell is functioning
normally. Functionally, the safeguards exist as proteins
known as cyclin-dependent kinases (CDK) and S-phase
promoting factor (SPF). The G1 CDK proteins activate the
transcription factors for a variety of genes. These include
genes (Fig. 8) which are responsible for DNA synthesis,
proteins and S-phase CDK proteins (Lodish et al., 2000).
Fig. 8:- Genome Structure
S (Synthesis) Phase of Cell Cycle
The S phase, short for synthesis phase, is a period in
the cell cycle during interphase between G1 phase and
the G2 phase. Following G1, the cell enters the S phase,
when
DNA
synthesis
or
replication
occurs.
At
the
beginning of the S stage, each chromosome is composed
of one coiled DNA double helix molecule, which is called a
chromatid. The enzyme DNA helicase splits the DNA
double helix down the hydrogen bonds (the middle
bonds).
DNA
polymerase
follows,
attaching
a
complementary base pair to the DNA strand, making two
new semi-conservative strands. At the end of this stage,
each chromosome has two identical DNA double helix
molecules, and therefore is composed of two sister
chromatids (joined at the centromere). During S phase,
the centrosome is also duplicated (Fig. 9). These two
events are unconnected, but require many of the same
factors to progress. The end result is the existence of
duplicated
genetic
material
in
the
cell,
which
will
eventually be divided into two (Hang et al., 2001).
Fig. 9:- Centrosome with Centrioles
Damage to DNA often takes place during this phase,
and DNA repair is initiated following the completion of
replication. Incompletion of DNA repair may flag cell cycle
checkpoints, which halts the cell cycle. However, after
the cell has completed this phase, it is very likely that the
cell will continue on to complete the cell cycle and a cell
that is not due to divide will not go through an S phase.
Rates of RNA transcription and protein synthesis are very
low during this phase. An exception to this is histone
production, most of which occurs during the S phase
(Nelson et al., 2002).
(Gap 2) Phase of Cell Cycle
The cell then enters the G2 phase, which lasts until
the
cell
enters
mitosis.
Again,
significant
protein
synthesis 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. It is
relatively a quiescent part of the cell cycle during
interphase, lasting from the end of DNA synthesis (the S
phase) until the start of cell division (the M phase).
G2 phase is final and usually the shortest subphase
during interphase within the cell cycle, in which the cell
undergoes a period of rapid growth to prepare for
mitosis. It follows successful completion of DNA synthesis
and chromosomal replication during the S phase, and
occurs during a period of often four to five hours (for
human cells). Thus the interphase nucleus is well defined,
bound by a nuclear envelope and contains at least one
nucleolus. Although chromosomes have been replicated,
they cannot yet be distinguished individually because
they are still in the form of loosely packed chromatin
fibers. The G2 phase prepares the cell for mitosis (M
phase) which is initiated by prophase. At the end of this
gap phase is a control checkpoint (G2 checkpoint), a
different Cdk-cyclin kinase complex (protein kinase)
termed the M-phase promoting factor(MPF), to determine
if the cell can proceed to enter M phase and divide. The
G2 checkpoint prevents cells from entering mitosis with
DNA damaged since the last division, providing an
opportunity for DNA repair and stopping the proliferation
of damaged cells. Because the G2 checkpoint helps to
maintain genomic stability, it is an important focus in
understanding the molecular causes of cancer.
G2 can be thought of as a safety gap during which a
cell can check to make sure that the entirety of its DNA
and other intracellular components have been properly
duplicated. In addition to acting as a checkpoint along
the cell cycle, G2 also represents the cell's final chance to
grow before it is split into two independent cells during
mitosis.
M Phase (Mitosis) of Cell Cycle
Mitosis is the process in which an eukaryotic cell
separates the chromosomes in its cell nucleus into two
identical sets in two daughter nuclei (Rubenstein et al.,
2008). It may also be defined as a type of cell division
within the body, whereby cells divide into other cells,
each with the full set of chromosomes. Each of these cells
receives an exact copy of the chromosomes in the
original cell. During development, mitosis occurs again
and again, until finally the adult organism is created.
Fig. 9-a: Eukaryotic Cell
The relatively brief M phase consists of nuclear
division
(karyokinesis)
and
cytoplasmic
division
(cytokinesis).
In
plants
and
algae,
cytokinesis
is
accompanied by the formation of a new cell wall.
When an eukaryotic cell divides into two, each daughter
or progeny cell must receive:
•
a complete set of genes (for diploid cells, this means
2 complete genomes, 2n)
•
a pair of centrioles (in animal cells)
•
some mitochondria (Fig. 13) and, in plant cells,
chloroplasts (Fig. 10) as well
•
some ribosomes (Fig. 12), a portion of the
endoplasmic reticulum (Fig. 11), and other
organelles
Fig. 10: Chloroplast
Fig. 11:- Endoplasmic Reticulum
Fig. 12:- Ribosome
Fig. 13:- Mitochondria
Karyokinesis and cytokinesis together constitute the
mitotic (M) phase of the cell cycle - the division of the
mother cell into two daughter cells, genetically identical
to each other and to their parent cell.
The process of mitosis is complex and highly
regulated. The sequence of events is divided into phases,
corresponding to the completion of one set of activities
and the start of the next. The M phase has been divided
into several distinct phases, sequentially known as:
•
•
•
prophase,
prometaphase,
metaphase,
•
•
•
anaphase,
telophase and
cytokinesis.
A brief description of each of these sub-stages of
mitosis is as follows:
Prophase
The first stage of mitosis during which chromosomes
condense, the nuclear envelope disappears, and the
centrioles divide and migrate to opposite ends of the cell
(Fig. 14)
Fig. 14:- Cells in The Prophase Stage
Changes that occur in a cell during prophase are:
•
The two centrosomes of the cell, each with its pair of
centrioles, move to opposite poles of the cell.
•
The mitotic spindle forms. This is an array of spindle
fibers, each containing 20 microtubules. Microtubules
are synthesized from tubulin monomers in the
cytoplasm and grow out from each centrosome.
•
The
chromosomes
become
shorter
and
more
compact.
•
The nuclear membrane starts disintegrating.
Prometaphase
Prometaphase is the phase of mitosis following
prophase and preceding metaphase in eukaryotic somatic
cells.
Changes that occur in a cell during prometaphase:
•
The nuclear envelope disintegrates because of the
dissolution
of
the
lamins
that
stabilize
its
inner
membrane. This is called open mitosis, and it occurs in
most multicellular organisms. Fungi and some protists,
such as algae or trichomonads, undergo a variation called
closed mitosis where the spindle forms inside the nucleus
or its microtubules are able to penetrate an intact nuclear
envelope (Ribeiro et al., 2004).
•
A protein structure, the kinetochore, appears at the
centromere of each chromatid. A kinetochore is a
complex protein structure that is analogous to a ring for
the microtubule hook; it is the point where microtubules
attach themselves to the chromosome (Chan et al.,
2005).
•
With the breakdown of the nuclear envelope, spindle
fibers attach to the kinetochores as well as to the arms of
the chromosomes. The kinetochore contains some form
of molecular motor. When a microtubule connects with
the kinetochore, the motor activates, using energy from
ATP
to
crawl
centrosome.
up
This
the
tube
motor
toward
activity,
the
originating
coupled
with
polymerisation and depolymerisation of microtubules,
provides the pulling force necessary to later separate the
chromosome's two chromatid (Maiato et al., 2004). When
the
spindle
grows
to
sufficient
length,
kinetochore
microtubules begin searching for kinetochores to attach
to. A number of nonkinetochore microtubules find and
interact with corresponding nonkinetochore microtubules
from the opposite centrosome to form the mitotic spindle
(Winey
et
al.,
1995).
Prometaphase
is
sometimes
considered part of the prophase.
•
Failure of a kinetochore to become attached to a
spindle fibre interrupts the process.
Metaphase
Metaphase comes from the Greek “meta” meaning
“after” As microtubules find and attach to kinetochores in
prometaphase, the centromeres of the chromosomes
convene along the metaphase plate or equatorial plane,
an imaginary line that is equidistant from the two
centrosome poles (Winey et al., 1995) (Fig.15). This
even alignment is due to the counterbalance of the
pulling powers generated by the opposing kinetochores,
analogous to a tug-of-war between people of equal
strength.
Because
proper
chromosome
separation
requires that every kinetochore be attached to a bundle
of microtubules (spindle fibres), it is thought that
unattached kinetochores generate a signal to prevent
premature
progression
to
anaphase
without
all
chromosomes being aligned. The signal creates the
mitotic spindle checkpoint (Chan and Yen, 2005).
Fig. 15:- Cells in Metaphase Stage
Changes that occur in a cell during metaphase
•
The nuclear membrane disappears completely.
•
In animal cells, the two of the pair of centrioles align at
opposite poles of the cell.
•
Polar fibres (microtubules that make up the spindle
fibres) continue to extend from the poles to the centre
of the cell.
•
Chromosomes move randomly until they attach (at
their kinetochores) to polar fibres from both sides of
their centromeres.
•
Chromosomes align at the metaphase plate at right
angles to the spindle poles.
•
Chromosomes are held at the metaphase plate by the
equal forces of the polar fibres pushing on the
centromeres of the chromosomes.
Anaphase
Anaphase, which has been from the ancient Greek
“ana” meaning “up”, is the stage of mitosis when
chromosomes
separate
in an
eukaryotic
cell.
Each
chromatid moves to opposite poles of the cell, the
opposite ends of the mitotic spindle, near the microtubule
organizing centres (Fig.16) During this stage, anaphase
lag could happen. Anaphase begins abruptly with the
regulated
triggering
of
the
metaphase-to-anaphase
transition and accounts for approximately 1% of the cell
cycle's duration. At this point the anaphase becomes
activated.
Fig. 16:- Cells in Anaphase Stage
Changes
that
occur
in
a
cell
during
anaphase
•
The paired centromeres in each distinct chromosome
begin to move apart.
•
Once the paired sister chromatids separate from one
another, each is considered a full chromosome. They
are referred to as daughter chromosomes.
•
Through
the
spindle
apparatus,
the
daughter
chromosomes move to the poles at opposite ends of the
cell (Fig.17).
•
The daughter chromosomes migrate centromere first
and the kinetochore fibres become shorter
•
In preparation for telophase, the two cell poles also
move further apart during the course of anaphase. At
the end of anaphase, each pole contains a complete
compilation of chromosomes.
Fig. 17:- Spindle Fibres with Centrioles
Telophase
Telophase, name derived from the Latin word “telos”
which means “end”, is a reversal of prophase and
prometaphase events. It may be defined as a period
wherein the chromosomes arrive at the poles, the
microtubules
disappear
reappears.
At
and
the
telophase,
the
nuclear
envelope
nonkinetochore
microtubules continue to lengthen, elongating the cell
even more (Fig. 18). Corresponding sister chromosomes
attach at opposite ends of the cell. A new nuclear
envelope, using fragments of the parent cell's nuclear
membrane, forms around each set of separated sister
chromosomes.
Both
sets
of
chromosomes,
now
surrounded by new nuclei, unfold back into chromatin.
Mitosis is complete, but cell division is not yet complete.
Telophase accounts for approximately 2% of the cell
cycle's duration.
Fig.18:- Cells in Telophase Stage
Changes that occur in a cell during telophase
•
The polar fibres continue to lengthen.
•
Nuclei (plural form of nucleus) begin to form at
opposite poles.
•
The nuclear envelopes of these nuclei are formed from
remnant pieces of the parent cell's nuclear envelope
and from pieces of the endomembrane system.
•
Nucleoli (plural form of nucleolus) also reappear.
•
Chromatin fibres of chromosomes uncoil.
•
After
these
changes,
telophase/mitosis
is
largely
complete and the genetic contents of one cell have
been divided equally into two.
Cytokinesis
Cytokinesis, name derived from the Greek “cyto” (cell) and “kinesis” (motion, movement), is the process in
which the cytoplasm of a single eukaryotic cell is divided
to form two daughter cells (Fig. 20). It may also be
defined as an organic process consisting of the division of
the cytoplasm of a cell following karyokinesis bringing
about the separation into two daughter cells. It usually
initiates during the late stages of mitosis, and sometimes
meiosis, splitting a binucleate cell in two, to ensure that
chromosome number is maintained from one generation
to the next. Cytokinesis is technically not even a phase of
mitosis, but rather a separate process, necessary for
completing cell division. In addition to dividing up the
cytoplasm,
cytokinesis
distributes
cellular
organelles
equally to the daughter cells. The binding of some
molecules or organelles to the chromosomes or spindle
microtubules ensures that each daughter cell will receive
a fair share of cytoplasmic components.
In animal cells, a cleavage furrow (pinch) containing
a contractile ring develops where the metaphase plate
used to be, pinching off the separated nuclei (Glotzer,
2005). In both animal and plant cells, cell division is also
driven by vesicles derived from the Golgi apparatus,
which move along microtubules to the middle of the cell
(Albertson et al., 2005). In plants this structure coalesces
into a cell plate at the centre of the phragmoplast and
develops into a cell wall, separating the two nuclei. The
phragmoplast is a microtubule structure typical for higher
plants, whereas some green algae use a phycoplast
microtubule array during cytokinesis (Raven et al.,
2005). Each daughter cell has a complete copy of the
genome of its parent cell. The end of cytokinesis marks
the end of the M-phase.
Cytokinesis must be temporally controlled to ensure
that it occurs only after sister anaphase separation during
normal proliferative cell divisions. To achieve this, many
components of the cytokinesis machinery are highly
regulated to ensure that they are able to perform a
particular function at only a particular stage of the cell
cycle.
Fig. 19:- Cells at Cytokinesis Stage