DNA Repair and Cancer Flashcards
(26 cards)
List types of DNA damage
- apurinic site
- mismatches between nitrogenous bases
- pyrimidine dimers
- intercalating agents
- interstrand crosslink
- double and single strand breaks
Give examples of sources that causes DNA damage
Exogenous sources :
- Ionising radiation
- Anti-cancer drugs
- Free radicals
Endogenous sources
- Replication errors
- Free radicals
Define DNA replication stress
Inefficient replication that leads to replication fork slowing, stalling and/or breakage
What causes DNA replication stress?
- Replication machinery defects
- Replication fork progression hindrance
- Defects in response pathways
Give an example of replication machinery defects
Misincorporation and proofreading
Explain Misincorporation and proofreading
- DNA polymerase elongates complimentary strand on 3’ end
- Mismatch removed by 3’ to 5’ DNA exonuclease
- 5’ to 3’ DNA polymerase occurs
Give examples of replication fork progression hindrance
- Repetitive DNA
- DNA lesions
- Ribonucleotide incorporation
Explain the events in repetitive DNA
Scenario 1 :
- Newly synthesised strand loops out
- 1 nucleotide added to new strand
- forming backward slippage
- second replication occur resulting in 2 (n+1) strands and 2 normal strands
Scenario 2 :
- Template strand loops out
- 1 nucleotide omitted on the new strand
- forming forward slippage
- second replication occur resulting in 2 (n-1) strands and 2 normal strands
State a disorder related to trinucleotide repeat
Huntington’s disease, Fragile X syndrome
Describe Huntington’s Disease
- Defect in HTT gene
- Normal - <35 CAG repeats
- Mutated - >35 CAG repeats
- results in neurone degeneration
What is the DNA Damage Response Pathway
- Damaged DNA produce signals
- sensor proteins receive signals and transmit to transducers (kinase)
- transducers phosphorylates other proteins which acts as effectors
List the example of responses during DNA damage
- Senescence
- apoptosis
- cell cycle checkpoints
- DNA repair
Where in the cell cycle does the cell cycle checkpoints occur?
- G1 : is environment favourable?
- G2 : are all DNA replicated? all damaged DNA repaired?
- M : are all chromosomes properly attached to mitotic spindle?
What are the different mechanisms for DNA repair?
- Base excision
- Nucleotide excision
- Mismatch
- Homologous-directed repair
- non homologous end joining (likely for mutation to occur)
When in the cell cycle does NHEJ and HR occur most?
G1 : NHEJ
S : HR
Describe the NHEJ process
- ends of double strand recognised by complex protein and rings are formed to protect ends
- another protein removes damaged ends
- broken ends ligated together
Briefly describe base excision
- deamination converts C to U
- U detacted and removed, nucleotide baseless
- baseless nucleotide removed, small hole in DNA backbone
- hole filled with right base by DNA polymerase
- sealed by ligase
Briefly describe nucleotide excision repair
- UV radiation causes Thymine dimers
- dimer detected, surrounding DNA opened, bubble formed
- enzymes cut the damaged region out of bubble
- DNA polymerase replaces excised DNA, ligase seals backbone
Briefly describe mismatch repair
- mismatch detected
- DNA strand cut (mispaired nucleotide + neighbours)
- DNA polymerase replaces excised DNA, ligase seals backbone
Describe HR process
- Resection
- DNA exonuclease cut segments (5’ to 3’) on each strand to produce 3’ over hang (provide hydroxyl group) - Invasion
- Strand invasion occur with homologous duplex
- D-loop formed
- 3’ end of invading strand act as primer for DNA synthesis
3. Formation of Holiday Junction Migration produces either non-crossovers products or crossovers products
What is the physiological cause of cancer?
Mutation accumulation in cell which induces replication stress
State the different stages of phases leading towards cancer
Normal cell –> hyper-proliferation –> early adenoma –> intermediate adenoma –> late adenoma –> carcinoma –> metastasis
Are cells tumours mostly homogenous or heterogenous? What are they called?
- Heterogenous
- Intra-tumour heterogeneity
Describe in two ways how tumours can still grow after chemotherapy?
- Differential sensitivity
- chemotherapy induced to tumour
- not effective to all cells
- surviving cells give immunity - clonal expansion
- tumour regrows - Chemotherapy-induced mutagenesis
- chemotherapy induce mutations in cells (tumour evolution promoted)
- causes cell to be resistant to anti cancer drug
