Cell Cycle
The cell cycle or
cell-division cycle is the series of events by which a cell divide into two
daughter cells. These events include duplication of DNA and organelles and partitioning
into two daughter cells.
Prokaryotic Cell Cycle
Cells, whether prokaryotic or eukaryotic, eventually
reproduce or die. For prokaryotes, the
mechanism of reproduction is relatively simple, since there are no internal
organelles. The cell cycle is divided into the B, C, and D periods. The B
period starts from the end of cell division to the beginning of DNA replication. This is the growth phase in which the mass of
the cell is increased. DNA replication occurs during the C period. The D period
starts from the end of DNA replication and is up to the splitting of the
bacterial cell into two daughter cells. The length of the overall cell cycle is
determined by the B period, as the C and D periods have relatively fixed time
constraints. The length of B is
determined mainly by environmental conditions and the gain in cell mass. Generation times for bacteria can vary from
under half an hour to several days.
Eukaryotic Cell Cycle
In eukaryotic cells, the
cell cycle is divided into two main stages: interphase and the mitotic (M)
phase. During interphase, the cell grows and accumulates nutrients needed for
mitosis, and replicates its DNA and some of its organelles. During the mitotic
phase, the replicated chromosomes, organelles, and cytoplasm separate into two
new daughter cells. To ensure the proper replication of cellular components,
there are control mechanisms known as cell cycle checkpoints in the cell cycle. These checkpoints determine if the cell can
progress to the next phase. Checkpoints prevent cell cycle progression at
specific points, allowing verification of necessary phase processes and repair
of DNA damage. The cell cannot proceed to the next phase until checkpoint
requirements are met. Checkpoints typically consist of a network of regulatory
proteins that monitor and dictate the progression of the cell through the cell
cycle.
Actively dividing eukaryote cells pass through a
series of stages in the cell cycle: two gap phases (G1 and G2); an S (synthesis)
phase, in which the genetic material is duplicated; and an M phase, in which
mitosis partitions the genetic material and the cell divides.
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Immediately following mitosis, the newly created cells are in the G1 phase. This is largely a growth phase, during which there is a lot of biosynthesis of proteins, lipids, and carbohydrates. There is no synthesis of new DNA at this time. G1 is the longest of the cell cycle phases in many cell types, and most of the physiological activity of a cell happens during G1.
Following G1, the next phase of the cell cycle is the
S phase, during which synthesis of new DNA occurs. The genome is being
replicated during this phase. At the end
of S phase, the cell has twice the normal amount of DNA.
After S phase, the cell proceeds into G2, which
provides an opportunity for the cell to perform a self-assessment and make
final preparations (such as more cell growth, repairing of DNA, etc) as
necessary before it finally heads into mitosis.
Mitosis, or M phase, is primarily
(1) Breakdown of the nucleus
(2) Re-distribution of the DNA to opposite sides of
the cell
(3) Formation of two new nuclei around that DNA, and
(4) Cytokinesis, the final splitting of the cell into
two.
·
G1 phase. Metabolic changes
prepare the cell for division. At a certain point - the restriction point - the
cell is committed to division and moves into the S phase.
·
S phase. DNA synthesis
replicates the genetic material. Each chromosome now consists of two sister
chromatids.
·
G2 phase. Metabolic changes
assemble the cytoplasmic materials necessary for mitosis and cytokinesis.
·
M phase. A nuclear division (mitosis)
followed by a cell division (cytokinesis).
The period between mitotic divisions - that
is, G1, S and G2 - is known as interphase.
As the cell progresses through the various phases of
cell cycle, it is through a specific and controlled manner, with checkpoints. These checkpoints “ask” if the cell is ready
for the next step: is it large enough, is the DNA healthy- without any damage,
etc. As a result, the cell ensures that it generate healthy daughter cells. If the cell cycle runs too rapidly without
the checkpoints, then there will not be enough time for the cell to enlarge, to
make up enough cellular organelles, etc and that may lead to abnormally small daughter
cells that fail to survive. Likewise, if a cell undergoes mitosis without
identifying and repairing damaged or mutated DNA, then the daughter cells may turn
into a cancerous cell. So it is very much necessary that the cell cycle is governed
by the check points.
Cell
cycle check points ensure that
- The nuclear genome
is intact and is without any damage
- The conditions are
appropriate to divide, there are enough nutrients for the daughter cells
- The genetic material
is divided only once in a cell cycle and is completely replicated
- No damages or
mutations in the daughter chromosomes, if there are mutations, will be
repaired by repair enzymes
- Chromosomes are
correctly aligned and oriented during metaphase and are correctly attached
to spindle fibers
The cell cycle is controlled at three checkpoints. The
integrity of the DNA is assessed at the G1
checkpoint. Proper chromosome duplication is assessed at the G2 checkpoint. Attachment of each
kinetochore to a spindle fiber is assessed at the M checkpoint. All the major
checkpoint transitions in the cell cycle is signaled by cyclins and cyclin
dependent kinases (CDKs). Cyclins are cell-signaling molecules that regulate
the cell cycle.
The G1 checkpoint
This is DNA damage checkpoint. This first checkpoint regulates the
transition from G1 to S phase. The G1
phase is the state of a cell immediately following cytokinesis, and is usually very
long. The length of G1 is generally
constant for a given cell type under normal conditions, but it vary greatly
between different cell types. Cell which
will no longer divide, are in G1 until they die, and this continuous G1-like
state is referred to as G0.
The G1 checkpoint determines whether conditions are
favorable for cell division to proceed. This checkpoint is also known as the
restriction point in yeast. During this
point the cell irreversibly commits to cell division. The cell will pass this
checkpoint only if it has an appropriate size and has favorable extracellular
environment and the cell also checks for DNA damage. The extracellular
environment includes nutrient availability or predatory threats and an external
trigger such as a mitogenic hormone or paracrine signal. Nearly all normal
animal cells require an extracellular signal to progress through the G1
checkpoint.
If a cell does not meet these requirements, it will
not progress to S phase. The cell will be halted in the cycle and attempt to
remedy the problematic conditions.
If a cell meets the requirements for G1 checkpoint, it
will enter S phase and begin DNA replication.
The
G2 checkpoint
This is DNA replication checkpoint. This
second checkpoint regulates entry of the into mitosis. This is triggered by MPF (Maturation
Promoting Factor or M-phase Promoting Factor) which is a cyclin-Cdk complex. It
promotes mitosis by phosphorylating a variety of other protein kinases.
Here also as with the G1 checkpoint, cell size and
protein/ energy reserves are assessed. The
most important role of this checkpoint is to ensure that all of the chromosomes
are accurately replicated without any mistake or damage.
If the checkpoint mechanisms detect problems with DNA,
this checkpoint hold the cell in G2 a little longer, the cell cycle is halted
and the cell attempts to either complete DNA replication or repair the damaged
DNA.
If no problems are detected with DNA, cyclin dependent
kinases (CDKs) signal the beginning of mitotic cell division. Most of the metabolic activity of the cell is
shut down, and cell concentrates its resources on dividing the nuclear and
cellular materials.
The
M checkpoint
This is the third checkpoint and occurs
during mitosis, near the end of the metaphase stage of mitosis. This regulates the transition from metaphase
into anaphase. It ensures that ail the
chromosomes are properly attached to the spindle at the metaphase plate before
anaphase. After attachment of all kinetochores, the anaphase promoting complex
(APC) is activated, triggering breakdown of cyclin and inactivation of proteins
holding sister chromatids together, and they split apart and move to opposite
poles.
The M checkpoint is also known as the spindle checkpoint because it
determines whether all the sister chromatids are correctly attached to spindle
microtubules. The cycle will not proceed until the kinetochores of each pair of
sister chromatids are firmly anchored to at least two spindle fibers arising
from opposite poles of the cell. This is
very important since the sister chromatids should be perfectly lined up at
metaphase, split apart and moved to opposite poles to form the new daughter nuclei. If they do not split evenly, the daughter
cells will have abnormal numbers of chromosomes (aneuploidy) and it leads to
deleterious consequences. Thus M
Checkpoint prevents cells from incorrectly sorting their chromosomes during
division.
Importance
of Cell cycle checkpoints
- Checkpoints delay
cell division until the problems are fixed and solved
- Checkpoints prevent
cell division if the problems cannot be solved
- Induce apoptosis if
the problems are severe and cannot be repaired
- Accurately maintain
the genome of the organism
- Ensures that only
one round of replication per cell cycle
- If checkpoints are
not working properly due to mutations, will lead to cancerous growth of
the cell
Regulatory
Molecules of the Cell Cycle
There are regulatory molecules which 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.
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
cyclins are proteins that regulate progression through the cell cycle. Cyclins
regulate the cell cycle when they are bound to respective cdk. To be fully active the cdk/cyclin complex
must be phosphorylated, then they phosphorylate other proteins that functions
in the cell cycle.
The levels of the four
cyclin proteins, Cyclin D, E, A and B, fluctuate throughout the cell cycle.
Increases in cyclin proteins are triggered by external and internal signals and
once the cell moves to the next stage of the cell cycle, the cyclins that were
active in the previous stage are degraded. There is a direct correlation
between cyclin accumulation and the three major cell cycle checkpoints.
Although the cyclins are the
main regulatory molecules that positively regulate cell cycle, there are several
other mechanisms to fine tune the cycle. These mechanisms block the progression
of the cell cycle until problem condition is solved. Molecules that prevent the
activation of cdks are called cdk inhibitors which directly or indirectly
monitor a particular cell cycle event. They block cdks until the specific event/error
being monitored is completed/repaired.
|
Cell cycle stage |
cyclins |
cdks |
comments |
|
G1 |
Cyclin D |
cdk 4 & 6 |
React to outside
signals such as growth factors or mitogens |
|
G1/S |
Cyclins E |
cdk 2 |
Regulate centrosome
duplication |
|
S |
Cyclins A |
cdk 2 |
Targets helicases and
polymerases |
|
M |
Cyclins B |
cdk 1 |
Regulate G2/M
checkpoint |
Negative Regulation of the Cell Cycle
The second group of cell
cycle regulatory molecules are negative regulators. Negative regulators halt
the cell cycle. Examples of negative regulatory molecules are retinoblastoma
protein (Rb), p53, and p21.
Rb, p53, and p21 act
primarily at the G1 checkpoint. p53 is a multi-functional protein, it acts when
there is damaged DNA 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. The protein p53 blocks the activity of Cdks and has
been dubbed as ‘Watchman’ or ‘guardian’ because DNA damage is sensed by it.
As p53 levels rise, the
production of p21 is triggered. p21 enforces the halt in the cycle by binding
to and inhibiting the activity of the Cdk/cyclin complexes. As a result, cell
will not move into the S phase.
Rb monitors cell size. In
the active, dephosphorylated state, Rb binds transcription factors, E2F. 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 and becomes
inactivated and releases E2F. E2F can
now turn on the gene that produces the transition protein and the G1/S
transition block is removed.
For the cell to move past
each of the cell cycle checkpoints, all positive regulators must be “turned on”
and all negative regulators must be “turned off.”
References
https://www.cureffi.org/2013/04/06/cell-biology-08-cell-cycle-regulation-and-checkpoints/
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