DNA Damage And Cell Cycle Checkpoints Flashcards
What are cell cycle checkpoints
Points where the cell checks if chromosomes are proper before moving one to the next step in the cycle
What happens if cells override the cell cycle checkpoints and there is still dna damage
Cancerous mutations
What are the 6 sources of every day dna damage
Uv from sun
Chemical carcinogens
Replication induced damage (due to replication)
X rays
Gamma rays
Radon gas
What are the potential ways to responding to dna damage
- Repair of the damage
- Activation of the dna damage checkpoint (to stop the cell cycle for repair)
- Or apoptosis (programmed cell death)
How does cancer come about
Due to unrepaired or poorly repaired dna damage
What are the causes of cell cycle arrest
The chromosomal dna is damaged
Critical events in the cycle are incomplete
Replication in S phase is incomplete
Alightment of chromosomes in M phase is improper
What is AT
What is ATM
An inherited recessive disorder
makes people sensitive to ionizing radiation, the gene encodes a protein kinase
AT-mutated, a kinase that is recruited when a double strand break happens in the dna
What is ATR
A protein kinase that is activated by dna damage from uv light
The damage is a single stranded dna break due to uv light
What 3 things can arrest the progression though the cell cycle at a checkpoint
Sensors
Transmitters/transducers
Effectors
What is a sensor
Give example
Detect chromosomal abnormalities (DNA damage)
ATM AND ATR
What are transmitters/transducers
They signal the information
Checkpoint kinases: CHK1 CHK2
What are effectors
Give example
Inhibit cell cycle machinery
p53 (guardian of the genome, tumor suppressor)
CDC25 (phosphatase that removes the WEE1 phosphate)
What does ATM protien kinase activate
And how is it activated
Activates CHK2 by phosphorylating it
Activated by ionizing radiation induced double strand breaks
What does ATR protien kinase activate
And how is it activated
Activates CHK1 by phosphorylating it
Activated by uv radiation induced single stranded breaks
What are the two dna damage checkpoints
The G2/M
G1-S
What checkpoint does ATM control
G1-S
What checkpoint does ATR control
G2/M
What is the G2/M Checkpoint
Stops cells from going to M phase when there is dna damage
Describe how ATR carried out the G2/M checkpoint arrest when there damage
Single stranded break due to uv
ATR phosphorylates CHK1 to activate it
CHK1phosphorylates the phosphatase cdc25 which moves cdc25 out of the cell and inactivated it
cdc25 inactivation caused cell cycle arrest because it can’t remove the tyr15 phosphate on the CDK
Where is the g1/S checkpoint
Between g1 and s phase
Describe how ATM carries out cell cycle arrest
Double strand break due to ionizing radiation activated ATM
ATM phosphorylates CHK2 and activated it
The active CHK2 stablizes p53 by phosphorylating it
Stable p53 transcribes p21 which inhibits the cdk
Cell cycle arrest
What is p21 and what does it do
It’s an inhibitor of the G1 cdk when the dna is damaged at the g1/s checkpoint
This makes it so the pRB is not phosphorylated since kinase is inhibited (need to be phosphorylated to let cell cycle continue)
Other than p21 what can p53 also transcribe
What does this do
Can transcribe cell death protiens
If repair isnt possible it help with cell death
Describe how pRB represses genes at g1/s ohase
In g1 E2F is bound to pRB on the promoter region of the dna
This is a repressive effect
When a cdk is active, it phosphorylates pRB and releases from E2F
This makes E2F an activator and the cell cycle cintinues
