Cell Cycle checkpoints

1. CELL CYCLE CHECKPOINTS
BY
K. RAVICHANDRAN

2. CELL CYCLE
 Cell pass through series of different stages in cyclic manner. The cyclic path of cellular
cyclic path of cellular events is called cell cycle. The length of the cell cycle is highly
cell cycle is highly variable, even within the cells of a single organism.
organism.
 Cell cycle leads to:
 Accurate duplication of genetic materials (DNA)
 Precise separation of replicated genetic materials
 Passing the genetic material in to two daughter cells
 The cell cycle is a four-stage process in which the cell increases in size (gap 1, or G1,
size (gap 1, or G1, stage), copies its DNA (synthesis, or S, stage), prepares to divide (gap
prepares to divide (gap 2, or G2, stage), and divides (mitosis, or M, stage). The stages G1,
stage). The stages G1, S, and G2 make up interphase, which accounts for the span
accounts for the span between cell divisions. On the basis of the stimulatory and
stimulatory and inhibitory messages a cell receives, it “decides” whether it should enter

3. Cell cycle checkpoints
 A checkpoint is a stage in the eukaryotic cell cycle at which the cell examines internal
and external cues and "decides" whether or not to move forward with division.
There are a number of checkpoints, but the three most important ones are:
 The G1​checkpoint (restriction checkpoint), at the G1/S transition.
 The G2 checkpoint (G2/M DNA Damage checkpoint).
 Metaphase (M) spindle checkpoint, at the transition from metaphase to anaphase.

4. Regulation at Internal Checkpoints

5. G0 Stage
Not all cells are continually replicating – some cells may enter
into a non-dividing G0 stage. These cells may either be dormant
(quiescent) or ageing and deteriorating (senescent). Cells enter the
G0 phase from the G1 phase; quiescent cells may re-enter G1 at a later
time (senescent cells do not). Normally, cells will only divide a finite
time before reaching senescence (a typical human cell will divide ~ 40
- 60 times). Specialised cells will often permanently enter G0, as
differentiation has prevented their capacity for further division.
Neurons are examples of cells that have been arrested in a G0 state –
these cells are amitotic (cannot divide)

6. G1 Checkpoint:
•Determine appropriate growth conditions (sufficient nutrients, cell
size, presence of growth factors, etc.). Assess level of DNA damage
(from ionizing radiation or UV)
G2 Checkpoint:
•Determine state of pre-mitotic cell (suitable cell size required for
successful division). Identify an replication faults (changes to DNA
sequence will distort genetic fidelity in daughter cells)
Metaphase Checkpoint:
•Ensure proper spindle assembly and correct attachment to centromeres
(prevents non-disjunction events)

7. What are the importance of cell cycle checkpoints?
• Checkpoint proteins delay the cell cycle progression until
problems are fixed
• Checkpoint can prevent cell division when problems cannot
be fixed
• Induce apoptosis if problems are so severe and cannot be
repaired
• Checkpoints accurately maintain the genome of the
organism
• Checkpoint ensure only one round replication of DNA per

8. Cell cycle
stage
Cyclins CDKs Comments
G1 Cyclin D CDK4&6
Can react to outside signals such as growth factors or
mitogens.
G1/S Cyclins E & A CDK2
Regulate centrosome duplication; important for
reaching START
S Cyclins E & A CDK2 Targets are helicases and polymerases
M Cyclins A & B CDK1
Regulate G2/M checkpoint. The cyclins are
synthesized during S but not active until synthesis is
complete. Phosphorylate lots of downstream targets.

9. Regulatory steps in the cell cycle  Cell starts in phase
G0 or G1.
1. DNA replication machinery begins to assemble at origins of replication
2. G1 cyclin-CDK complexes inactivate Cdh1
3. G1 cyclin-CDK complexes activate the S-phase cyclin-CDK expression
4. G1 cyclin-CDK complexes phosphorylate and thereby inactivate S-phase
inhibitor(s?)
5. SCF polyubiquitinates the phosphorylated S-phase inhibitor, targeting it for
proteasome degradation. Cell enters S phase.
6. S-phase cyclin/CDK activates the preplication complexes that began to assemble
in step 1. S phase and G2 phase happen.
7. Cdc25 phosphatase activates M-phase cyclin/CDKs. Cell enters M phase and
gets to metaphase.
8. APC/C and Cdc20 target securin for proteasomal degradation. Cell advances
from metaphase to anaphase.