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CELL CYCLE IN CANCER CELL & DNA REPAIR MECHANISM, Cancer Cell Cycle vs…
CELL CYCLE IN CANCER CELL & DNA REPAIR MECHANISM
P53
(Tumor suppressor)
P53 is a gene encoded for protein to regulate cell cycle and responsible to suppress tumor formation
Located at chromosome 17
Its name is due to the molecular mass is 53 kilodalton (kDa) proteins.
An important downstream target of ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) to induce apoptosis following DNA damage.
P53 deactivate the CDK2/cyclin E complex at G1/S phase
Cell death in cancer
(Apoptosis deactivation)
Entrinsic pathway (Mitochondrial)
DNA damage
Caspases Enzyme
Apoptosis inhibitors
IAP protein
Bcl-2 family
Apoptosis inhibited
Main Method In DNA Repair
Mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
Excision repair
(a) Base excision
-DNA's bases may be modified by deamination or
akylation
-The DNA glycosylase can recognize the damaged site and
remove its base forming AP site Apurinic Apyrimidinic
-Then, the AP endonuclease removes the AP site and
neighboring nucleotides
-The gap is filled by DNA polymerase I and DNA ligase
a)Each DNA glycosylase is generally specific for one type of lesion.
b)Humans have at least four types glycosylase with different
specifictices
(b) Nucleotide Excision Repair (NER)
It uses different enzymes
Even thought there may be only single ''bad'' base to correct
, its nucleotide is remove along with many other adjacent nucleotides ; that is ,NER removes a large patch around the damage
Recombinant repair
Homologous recombination repair (HRR)
• Here the broken ends are repaired using the
information on the intact sister chromatid or on the homologous
chromosome.
• Two primary models:
DSBR pathway
The synthesis-dependent strand annealing (SDSA)
pathway.
Nonhomologous Recombinant
Repair (NHRR)
• Also known as Nonhomologous End-Joining (NHEJ) or
direct joining:
• Direct joining of the broken ends.
• This requires proteins that recognize and bind to the
exposed ends and bring them together for ligating.
• They would prefer to see some complementary
nucleotides but can proceed without them
• Errors in direct joining may be a cause of the various
translocations that are associated with cancers.
• Homologous recombination repairs DNA before the cell
enters mitosis (M phase).
• It occurs during and shortly after DNA replication, in the
S and G2 phases of the cell cycle
• NHRR is predominant in the G1 phase of the cell cycle, when the cell is growing but not yet ready to
divide.
Cancer Cell Cycle vs Healthy
After DNA damage, cell cycle checkpoints are activated
checkpoint activication pauses the cell cycle and gives the cell time to repair the damage before continuing to divide
Cancer cells don't stop growing and dividing, this uncontrolled cell growth results in the formation of a tumor.
Normal cells only grow when they receive such signals. ignore signals that normally tell cells to stop dividing or to die (a process known as programmed cell death, or apoptosis).
ubiquitin-proteasome pathway
Activation of transcription factors
Nuclear Factor (NF-kB)
Proteasome
NF-kB inhibitor
Stimulate
