Cancer Bio (Dan Lecture 3 - DNA damage) Flashcards

1
Q

Name come common types of DNA damage?

A
  • Oxidation
  • Methylation
  • Strand breaks
  • Bulky adducts
  • Cross links
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2
Q

Name some DNA damaging agents

A
  • UV
  • Cigarette smoke
  • Dyes
  • Ionising radiation
  • Chemotherapy
  • Foods?
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3
Q

Name some types of endogenous DNA damage

A
  • Deamination (e.g. cytosine to uracil)
  • Oxidation
  • Methylation
  • Lipid peroxidation
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4
Q

Name some types of exogenous DNA damage

A
  • Pollutants
  • UV
  • Ionising radiation
  • Ciggy smoke
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5
Q

Name the repair processes responsible for the repair of the following:

1) Oxidative damage and SSBs
2) Bulky adducts, CPDs and 6-4PPS
3) Cross links and DSBs
4) Mismatches, insertions or deletions

A

1) Base-excision repair
2) Nucleotide excision repair
3) Recombinational repair
4) Mismatch repair

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6
Q

What are the potential consequences if DNA damage is not repaired?

A

1) Cell cycle arrest
2) Apoptosis
- caused by inhibition of transcription, replication or chromosome segregation
3) Cancer, Ageing
- Caused by mutations and chromosome abrrations

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7
Q

What are the 3 classifications of UV radiation and what is the wavelength of each?

A

UVA (320-400nm)
UVB (295-320nm)
UVC (100-295nm)

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8
Q

Why does solar radiation contain 95% UVA with the rest UVB?

A

Because the ozone absorbs UV with wavelength below 300nm

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9
Q

What year was UV classified as a human carcinogen and by which body?

A

Internation Agency for Research on Cancer 1992

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10
Q

What are the 3 types of skin cancer and what are the characteristics of each?

A

1) Basal cell carcinoma
- Relatively common
- Can be invasive
- Rarely metastatic

2) Squamous cell carcinoma
- Less common
- Significant risk of metastasis to lymph nodes

3) Melanoma - affecting melanocytes
- Rare
- Highly invasive
- Common metastasis
- 75% of skin cancer death attributed to melanoma

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11
Q

Describe the penetrance of different UV types

A

UVA is lower energy but has higher penetrance than UVB

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12
Q

What countries have the highest rates of skin cancer?

A

Australia and New Zealand

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13
Q

Why are skin cancer rates so high in Australia and NZ?

A

1) Thin layer of ozone
- allows more UV exposure

2) Culture
- Outdoor lifestyles
- Fashion of the tan
- Society of not applying sun cream
- Slip, slop, slap campaign in 1981 to try and introduce sun protection into Australian society

3) Skin tone
- Movement of fair skinned Europeans in 18th century

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14
Q

What are the main 2 types of cancer relevant DNA damage induced by UV?

A

1) Cyclobutane pyrimidine dimers (CPD)

2) (6-4) pyrimidine-pyrimidone photoproducts (6-4PPS)

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15
Q

What is the structure of CPDs and 6-4PPs?

A

CPDs:

  • covalent link between adjacent pyrimidine bases
  • due to saturation of 5,6 double bonds, predominantly in the cis-syn conformation

6-4PPs:
- linking the C6 of the 5’ pyrimidine with the C4 of the 3’ pyrimidine

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16
Q

What other damage does UVA and B cause?

A
  • Oxidative damage

- Protein distortion

17
Q

What can happen as a result of UV induced DNA damage?

A
  • Cell cycle arrest pre S phase, reducing copying errors
  • Extensive damage leading to apoptosis
  • Damage repair by NER

IF THESE DO NOT HAPPEN:

  • Cells enter S phase
  • Copying errors introduced, leading to mutations
18
Q

What is the definition of a mutation?

A

Heritable change in the sequence of an organisms DNA

19
Q

What is the definition of a mutagen?

A

An agent that leads to an increase in the frequency of mutations

20
Q

What is the definition of mutagenesis?

A

The process by which mutations are introduced

21
Q

What is the most common UV induced DNA mutation?

A

Pyrimidine dimers cause CC to TT transitions

- Hallmarks of certain skin cancers, especially non-melanomas

22
Q

What process repairs pyrimidine dimers?

A

Nucleotide excision repair

23
Q

What are the 2 types of NER and what are the characteristics of each?

A

1) Global genomic NER
- deals with whole genome

2) Transcription-coupled NER
- Faster repair in highly transcribed genes

24
Q

Describe the process of lesion recognition in GGNER and TCNER

A

GG-NER:

  • helix distortion recognised by XPC complex
  • CPDs do not cause as much helix distortion so require assistance by XPE and the UV radiation-DNA damage-binding protein (UV-DDB)

TC-NER:

  • Lesions causes RNA polymerase II to stall
  • Acitvation of CSB protein
25
Q

Describe the rest of the NER process (conserved in both types)

A

DNA unwinding:

  • TFIIH binds XPC
  • TFIIH subunits XPB and XPD have helicase activity and unwind DNA

Scaffold support:

  • XPA binds to damaged strand
  • RPA binds to undamaged strand

Excision:

  • XPF-ERCC1 binds and cleaves 5’ side of lesion
  • XPG binds and cleaves 3’ side

DNA synthesis and ligation:

  • Binding of RFC and sliding clamp PCNA
  • Facilitates activity of DNA polymerase δ or ε
  • Ligation by DNA ligase I
26
Q

What is Xeroderma Pigmentosum (XP) and what are the symptoms?

A
  • Rare autosomal recessive disorder in GG-NER
  • Extreme sensitivity to sunlight
  • Freckle-like pigmentation in sen-exposed areas
  • 10,000 fold increase in non-melanoma skin cancer
  • 2,000 fold increase in melanoma
27
Q

What causes XP?

A
  • Mutations in XPA-XPG genes

- Results in dysfunctional XPA-XPG proteins

28
Q

What are XP complementation groups?

A

Different types of XP dependent on the XP protein/s that are affected
i.e Complementation group A = XPA affected

29
Q

Which complementation groups gives less severe phenotypes?

A
  • Severity of disease depends on complementation group
  • Some give neurological problems
  • XPC and XPE groups give milder phenotype and no neurological disorders
30
Q

How is p53 involved in repair of CPDs?

A
  • CPDs cause significantly less helix distortion
  • 6-4PPs recognised by XPC and repaired faster than CPDs
  • p53 regulates CPD repair by upregulation of XPE
31
Q

Cisplatin is commonly used to treat which cancers? What is its mechanism of action?

A

Testicular and ovarian

Causes DNA adducts, primarily intrastrand crosslink adducts

32
Q

How is NER adapted to cause cisplatin resistance?

A
  • Resistant cells enhance ERCC1
  • Enhanced ERCC1 leads to enhanced NER
  • Greater reapir of cisplatin induced DNA adducts