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Y2 Cancer > DNA Damage and Repair > Flashcards

DNA Damage and Repair Flashcards

1
Q

What is deamination and give examples

A

Primary amino groups of nucleic acid bases can be converted to ketogroups (C->U)
Adenine -> hypoxanthine
Guanine -> xanthine
5-methyl cytosine -> thymine

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2
Q

What is chemical modification

A

Nucleic acid bases are susceptible to modifications by a wide variety of chemical agents
Common for Adduct formation
Several types of hyper-reactive oxygen (singlet oxygen, peroxide radicals, hydrogen peroxide and hydroxyl radicals) can modify DNA bases

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3
Q

What is a common product of thymine oxidation

A

Thymine glycol

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4
Q

How can hyper-reactive oxygen species be generated

A 
As byproducts during normal oxidative metabolism
Ionising radiation (x-rays, gamma rays)
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5
Q

How do environmental chemicals modify DNA bases

A

Addition of methyl or alkyl groups

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6
Q

What is photodamage

A

Ultraviolet light is absorbed by the nucleic acid bases

The resulting influx of energy can induce chemical changes

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7
Q

What are the most frequent photoproducts

A

Consequences of bond formation between adjacent pyrimidines within one strand.

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8
Q

What are the types of DNA damage

A

Nick
Gap
Thymine dimer
Base pair mismatch

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9
Q

What carcinogens can cause to damage DNA

A 
dietary
lifestyle
environmental
occupational
medical
endogenous
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10
Q

Which types of radiation can damage DNA

A

ionizing
solar
cosmic

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11
Q

Describe the DNA damage by carcinogens

A

DNA adducts and alkylation
Base hydroxylations
Base dimers and chemical cross-links
Double and single strand breaks

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12
Q

Describe the phases of metabolism

A

Phase I - addition of functional groups
Mainly cytochrome P450-mediated

Phase II - Conjugation of phase I functional groups 
Generates polar (water soluble) metabolites
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13
Q

Give examples of Phase I reactions

A

Oxidation
Reduction
Hydrolysis

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14
Q

Give examples of phase II reactions

A 
Sulphation
Glucuronidation 
Acetylation
Methylation
Amino acid 
Glutathione conjugation
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15
Q

Where can polycyclic aromatic hydrocarbons, aflatoxin B1 and 2-napthylamine be found

A

Polycyclic hydrocarbons - Formed from combustion of fossil fuels and tobacco

Aflatoxin B1 - grains and peanuts

2-napthylamine - Dye-stuffs (past)

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16
Q

Describe the epoxidation of B[a]P

A

2 steps
B[a]P is converted to DNA adducts using liver P450 and epoxide hydrolase
DNA adducts attaches itself to bases and causes mutations

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17
Q

Describe the epoxidation of aflatoxin B1

A

Conversion first by cytochrome p450 oxidase into a very active form.
Reaction with guanine on DNA (N7 position) to cause adduct formation

18
Q

Describe the metabolism of 2-naphthylamine

A

First conversion by cytochrome p450 oxidase (CYP1A2)
Second is a phase II reaction using glucuronyl transferase
pH of the urine causes conversion to a DNA-reactive electrophile that causes bladder tumours

19
Q

What is an adduct

A

Segment of DNA bound to a cancer-causing chemical

Often from the conversion of a small molecule to a much larger one

20
Q

Explain how UV radiation is able to damage DNA

A

Pyrimidine (thymine) dimers

Skin cancer

21
Q

Explain how ionising radiation is able to damage DNA

A

Generates free radicals in cells
Includes oxygen free radicals
super oxide radical (O2•)
hydroxyl radical (HO•)

Possess unpaired electrons
electrophilic and therefore seek out electron-rich DNA

22
Q

Describe the oxygen free radical attack on DNA

A

Double and single strand breaks
Apurinic + apyrimidinic sites (reactive)
Base modifications

23
Q

What are the base modifications that oxygen free radicals can cause

A

ring-opened guanine +adenine
thymine + cytosine glycols
8-hydroxyadenine + 8-hydroxyguanine (mutagenic)

24
Q

What is the role of p53 in dealing with cellular stress

A 
(tumour suppressor gene)
Responds to cellular insults:
Mitotic apparatus dysfunction 
DNA replication stress
Double-Strand breaks

MDM2 keeps p53 inactive. It is then lost in damage, allowing p53 to activate transcriptional pathways, including DNA repair

25
Q

What are the types of DNA repair

A

Direct reversal of DNA damage
Base excision repair (mainly for apurinic/apyrimidinic damage)
Nucleotide excision repair (mainly for bulky DNA adducts)
During or post replication repair

26
Q

Describe direct DNA repair

A

the reversal or simple removal of the damage by the use of proteins which carry out specific enzymatic reactions

27
Q

What is the actions of MGMT and photolyases

A

directly reverses some simple alkylation adducts

Photolyases repair thymine dimers

28
Q

How are DNA mismatches repaired

A

Involves scrutinisation of DNA for apposed bases that do not pair properly
Mismatches that arise in replication are corrected via proof-reading (comparison of old and new) - preference for the new strand
Other systems deal with mismatches generated by base conversions, such as those which result from deamination

29
Q

Describe base excision repair of DNA damage

A

Damage to base (but not to the phosphodiester backbone)

  1. DNA glycosylase removes the base of the nucleotide without affecting the backbone
  2. AP-endonuclease cuts the DNA strand open
  3. DNA polymerase adds the correct base
  4. DNA ligase closes the strand
30
Q

Describe the nucleotide excision repair of DNA damage

A
  1. Endonuclease removes the phosphodiester bond
  2. Helicase removes a large chunk of bases (including backbone)
  3. DNA polymerase remakes the strand
  4. DNA ligase closes strand
31
Q

Give examples of human genetic disease involving nucleotide excision repair

A

Xeroderma pigmentosum
Trichothiodystrophy
Cockayne’s syndrome

32
Q

When are double-strand breaks made

A

Under physiological conditions during somatic recombination and transposition. e.g. V(D)J recombination

During Homologous Recombination.

As a result of ionizing radiation and oxidative stress induced DNA damage.

33
Q

Describe DNA double strand break repair

A

Direct joining of the broken ends. This requires proteins that recognize and bind to the exposed ends and bring them together for ligating.
Non-complementary nucleotides - Nonhomologous End-Joining (NHEJ).

34
Q

What are the consequences of incorrectly repaired carcinogen damage leading to altered DNA

A

DNA replication and cell division -> fixed mutation
Transcription/translational gives aberrant proteins
Carcinogenesis if the targets are mutated
Apoptosis and cell death

35
Q

What are the types of therapeutic agents used to cause DNA damage in tumour cells

A

Alkylating agents
Agents that make bulky adducts
Agents that induce double strand breaks

36
Q

How is DNA damage tested for

A
  1. Structural alerts/SAR
  2. In vitro bacterial gene mutation assay
  3. in vitro mammalian cell assay
  4. in vivo mammalian assay
  5. Investigation in vivo mammalian assays
37
Q

Describe the Ames test for mutagenicity of chemicals

A

The chemical tested is added to rate liver enzyme preparations (S9) and bacteria that do not synthesise histidine
Conversion of chemical to reactive metabolite
On histidine-free media: if mutations occur in bacterial genome
then bacteria acquire ability to synthesise histidine = colonies

38
Q

Give an example of a bacterium that does not synthesise histidine

A

Salmonella

39
Q

How are chromosomal aberrations detected

A

Treat mammalian cells with chemical in presence of liver S9. Look for chromosomal damage

40
Q

Describe the in vitro micronucleus assay

A

Cells treated with chemical and allowed to divide
Binucleate cells assessed for presence of micronuclei
Can stain the kinetochore proteins to determine if chemical treatment caused clastgenicity (chromosomal breakage) or aneuploidy (chromosomal loss)

41
Q

Describe the murine bone marrow micronucleus assay

A

Treat animals with chemical and examine bone marrow cells or peripheral blood erythrocytes for micronuclei

Y2 Cancer (16 decks)

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