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MCBG > DNA Repair and Cancer > Flashcards

DNA Repair and Cancer Flashcards

1
Q

List types of DNA damage

A
  • apurinic site
  • mismatches between nitrogenous bases
  • pyrimidine dimers
  • intercalating agents
  • interstrand crosslink
  • double and single strand breaks
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2
Q

Give examples of sources that causes DNA damage

A

Exogenous sources :

  • Ionising radiation
  • Anti-cancer drugs
  • Free radicals

Endogenous sources

  • Replication errors
  • Free radicals
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3
Q

Define DNA replication stress

A

Inefficient replication that leads to replication fork slowing, stalling and/or breakage

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4
Q

What causes DNA replication stress?

A
  • Replication machinery defects
  • Replication fork progression hindrance
  • Defects in response pathways
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5
Q

Give an example of replication machinery defects

A

Misincorporation and proofreading

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6
Q

Explain Misincorporation and proofreading

A
  • DNA polymerase elongates complimentary strand on 3’ end
  • Mismatch removed by 3’ to 5’ DNA exonuclease
  • 5’ to 3’ DNA polymerase occurs
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7
Q

Give examples of replication fork progression hindrance

A
  • Repetitive DNA
  • DNA lesions
  • Ribonucleotide incorporation
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8
Q

Explain the events in repetitive DNA

A

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
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9
Q

State a disorder related to trinucleotide repeat

A

Huntington’s disease, Fragile X syndrome

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10
Q

Describe Huntington’s Disease

A
  • Defect in HTT gene
  • Normal - <35 CAG repeats
  • Mutated - >35 CAG repeats
  • results in neurone degeneration
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11
Q

What is the DNA Damage Response Pathway

A
  1. Damaged DNA produce signals
  2. sensor proteins receive signals and transmit to transducers (kinase)
  3. transducers phosphorylates other proteins which acts as effectors
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12
Q

List the example of responses during DNA damage

A
  • Senescence
  • apoptosis
  • cell cycle checkpoints
  • DNA repair
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13
Q

Where in the cell cycle does the cell cycle checkpoints occur?

A
  • G1 : is environment favourable?
  • G2 : are all DNA replicated? all damaged DNA repaired?
  • M : are all chromosomes properly attached to mitotic spindle?
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14
Q

What are the different mechanisms for DNA repair?

A
  1. Base excision
  2. Nucleotide excision
  3. Mismatch
  4. Homologous-directed repair
  5. non homologous end joining (likely for mutation to occur)
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15
Q

When in the cell cycle does NHEJ and HR occur most?

A

G1 : NHEJ

S : HR

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16
Q

Describe the NHEJ process

A
  1. ends of double strand recognised by complex protein and rings are formed to protect ends
  2. another protein removes damaged ends
  3. broken ends ligated together
17
Q

Briefly describe base excision

A
  • 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
18
Q

Briefly describe nucleotide excision repair

A
  • 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
19
Q

Briefly describe mismatch repair

A
  • mismatch detected
  • DNA strand cut (mispaired nucleotide + neighbours)
  • DNA polymerase replaces excised DNA, ligase seals backbone
20
Q

Describe HR process

A
  1. Resection
    - DNA exonuclease cut segments (5’ to 3’) on each strand to produce 3’ over hang (provide hydroxyl group)
  2. 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
21
Q

What is the physiological cause of cancer?

A

Mutation accumulation in cell which induces replication stress

22
Q

State the different stages of phases leading towards cancer

A

Normal cell –> hyper-proliferation –> early adenoma –> intermediate adenoma –> late adenoma –> carcinoma –> metastasis

23
Q

Are cells tumours mostly homogenous or heterogenous? What are they called?

A
  • Heterogenous

- Intra-tumour heterogeneity

24
Q

Describe in two ways how tumours can still grow after chemotherapy?

A
  1. Differential sensitivity
    - chemotherapy induced to tumour
    - not effective to all cells
    - surviving cells give immunity - clonal expansion
    - tumour regrows
  2. Chemotherapy-induced mutagenesis
    - chemotherapy induce mutations in cells (tumour evolution promoted)
    - causes cell to be resistant to anti cancer drug
25
Q

Give an example of synthetic lethality strategy

A

PARP inhibitors for breast cancer

26
Q

How does PARP inhibitors work?

A
  1. Normal cell :
    - Normal cell BRCA 1/2 +/- has SSB (single strand breaks)
    - PARP inhibitor causes SSB to be DSB
    - repair mechanism - cell survive
  2. Tumour cell BRCA 1/2 -/-
    - no repair mechanism for DSB
    - tumour dies

MCBG (7 decks)

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