DNA Repair and Cancer Flashcards
5 Exogenous sources of Dna damage
ionising radiation
Alkylating agents (stop replication)
Mutagenic Chemicals
Anti-cancer drugs
Free radicals
What is DNA replication stress?
Inefficient replication that leads to replication fork slowing, stalling and or breakage.
Misincorporation of base pairs and proofreading
When DNA polymerase adds base pairs sometimes theres an error, they are normally quickly and efficiently fixed by 3’to 5’ DNA exonuclease removing bad match.
hindrance of replication fork progression.
MAYBE COME BACK TO?
Fork slippage
Where repetitive DNA sequence leads to additional or few Base pairs, eg 5 As in a row, might only get 4 Ts coded, or may get 6 as one strand slips.
DNA repair pathway steps
signals
sensors
transducers
effectors
2 Types of DNA break
Single
Double
What is senescence?
Cell gets old
Cell cycle Checkpoints
G2, allows temporary arrest to repait DNA just before mitosis.
G1, checks for favourable environment before S phase.
3 Types of DNA repair mechanisms
Base or Nucleotide excision repair
Recombination
Mismatch repair
3 types of single strand break repair
Base excision
Nucleotide excision repair
mismatch repair
Base excision repair
If cytosine base turns into uracil via deamination, uracil is detected and removed, baseless nucleotide is removed, leaving hole in backbone, Hole refilled with correct base by DNA polymerise, Gap sealed by a ligase.
Nucleotide excision repait
UV radiation causes a dimer, dimer detected, surrounding DNA opened (strands around separated, forming a bubble)
enzymes cut damaged region out of the bubble
DNA polymerase replaces excised DNA, ligase seals backbone.
Mismatch repair
mismatch found in newly synthesised DNA, new DNA strand cut, mismatched nucleotide and neighbours removed, missing patched replaced by DNA polymerase, DNA ligase repairs backbone.
Double strand break repair methods
non homologous end joining
homology directed repair
Non homologous end joining
Broken ends bound by proteins.
excess base pairs trimmed
put back together ligase repairs.
MIGHT NOT BE EXACT COPY, SOME MIGHT HAVE BEEN REMOVED
Homology directed repair
DNA either side resected (cut out)
DNA uses sister chromatid to rematch broken section
ligase reconstructs
mutations in DNA repair and cancer
Cancer formation requires multiple mutations over time, to form malignancies
Lynch syndrome.
What disease does it increase the risk of?
What is its other name?
What causes the probelms?
Also known as Hereditary nonpolyposis colorectal cancer.
Inherited disorder which increases chance of colorectal cancer. As well as other cancers. Women more likely to get cancer as a result of disorder because cancers of their reproductive tract is also affected. - Ovaries and Uterus.
Multiple mutations required for malignancy.
Initial mutation leads to hyperproliferation, which is then turned into an adenoma, then a carcinoma by lots of mutations
DNA mismatching repair problem in lynch syndrome.
Problem with chemo and heterogenous cancer cells
Differential sensitivity, due to varying differences, expansion of resistant genous
Irrespective of hetergenous nature, chemo itself can cause mutations in tumours, causing resistance itself.
What does cancer evolution cause
Intertumour and intratumour heterogeneity
Synthetic lethality strategies
In normal cells there is redundancy in genetic pathways, they have gene a and b for the same function. In cancers where gene a has mutated, you can look for a disabler of gene B, therefore depriving cancer cells of a pathway.
Example of synthetic lethal strategy
PARP inhibitors in breast cancer.
Ataxia Telangiectasia, What method of inheritance?
What is the mutated gene?
What are the symptoms
Inherited autosomal recessively - more likely to occur as result of co sanguinity- found more in cultures with cousin marriage
Mutation in the ATAXIA TELANGIECTASIA MUTATED gene. leads to a failure of homology directed repair
small cerebellum, sensitivity to UV
