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Cancer Y2 > DNA Damage and Repair > Flashcards

DNA Damage and Repair Flashcards

1
Q

How many copies of a TSG need to be mutated to drive mutation? Exception?

A

2, except from p53

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2
Q

What chemical sources of DNA damage are there (6)

A
  • Dietary- 40% of all human cancer associated with diet (includes drinking)
  • Lifestyle- Alcohol consumption, smoking (1/6 people) etc.
  • Environmental
  • Occupational
  • Medical- Drugs, X-rays etc.
  • Endogenous
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3
Q

What radiative sources of DNA damage are there

A
  • Ionising
  • Solar – e.g. Australia has a high rate of skin cancer due to Caucasian immigrants, and also UV beds etc.
  • Cosmic- The higher you go, the more cosmic radiation you get e.g. flying
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4
Q

4 ways DNA is damaged by carcinogens?

A
  1. DNA adducts and alkylation
  2. Base dimers and chemical cross-links
  3. Base hydroxylations and abasic sites formed
  4. Double and single strand breaks – quite frequent, double strand breaks are the worst damage you can do
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5
Q

What is the worst type of DNA damage

A

Double strand breaks

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6
Q

What is a common form of DNA damage

A

single strand breaks

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7
Q

What reactions take place in phase 1 metabolism of drugs, what mediates this

A
  • Addition of functional groups:
    e. g. oxidations, reductions, hydrolysis
  • Mainly cytochrome p450-mediated
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8
Q

What are phase 2 reactions called generalised, what are the 6 different reactions and what is the aim of it

A
  • Conjugation of Phase I functional groups:
    e. g. sulphation, glucoronidation, acetylation, methylation, amino acid and glutathione conjugation
  • Generates polar metabolites which can be excreted easily as it’ll dissolve in water.
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9
Q

what are polycyclic aromatics formed from

A
  • Formed from combustion of fossil fuels and tobacco
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10
Q

What feature of polycyclic aromatics structure makes them carcinogenic

A
  • The aromatic ring makes it quite electron rich
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11
Q

Example of a polycyclic aromatic? (3)

A

Benzo[A]Pyrene
AFLATOXIN B1
2-NAPHTHYLAMINE

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12
Q

How does Benzo[A]Pyrene cause mutations via its metabolysm

A
  1. Metabolised by cytochrome p450 which oxidises it into an epoxide (or oxide)- unstable
  2. Epoxide hydrolase splits the ring to form 2 alcohol-type molecules- this is now harmless
  3. 2nd p450 oxidation forms a diol-epoxide Very unstable so decomposes spontaneously
  4. This rapidly forms +ve carbon atoms which then form DNA adducts (usually at guanine) Mutation
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13
Q

What does Benzo[A]Pyrene become thats carcinogenic

A

diol-epoxide

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14
Q

What type of DNA damage does Benzo[A]Pyrene cause

A

DNA adducts

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15
Q

What forms AFLATOXIN B1

A
  • Formed by Aspergillus flavus mould

- Common on poorly stored grains and peanuts

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16
Q

What can exposure to aflatoxin b1 cause

A

hepatocellular carcinoma due to its effects on CYP450

17
Q

What was 2-NAPHTHYLAMINE used in in the past

A

Dyes

18
Q

How does OF 2-NAPHTHYLAMINE cause cancer

A
  • Amino group is a substrate for p450, then the product is detoxified by hepatic glucuronyl transferase
  • Then excreted into the urine, but the urine acidic pH causes loss of sugar, which causes it to become reactive producing a nitrenium ion and cause bladder cancer
19
Q

What type of cancer does 2-NAPHTHYLAMINE cause

A

Bladder

20
Q

How does UV light cause cancer

A
  • UV light induces pyrimidine (thymine) dimers UV light causes crosslinks to form between pyrimidines in DNA- cell tries to repair this, but introduces a mutation
  • Causes high incidence of skin cancer
21
Q

How does ionising radiation cause the regeneration of 2 free radicals (which radicals)

A

Ionising radiation activates oxygen to form super oxide radicals (oxygen has gained an electron- very reactive) and hydroxyl radicals (same again)

22
Q

How does ionising radiation cause cancer (think type of damage (2), and what they form

A

Oxygen and hydroxyl free radicals attack DNA.
Generate double and single strand breaks via apurinic and apyrimidinic sites where the base is actually stripped out of the DNA. When the stripped DNA is attempted to be repaired there is a chance for incorrect mutations.
Also introduce base modifications:
- Open rings of guanine and adenine
- Form thymine and cytosine glycols
- Hydroxylate purines to form 8-hydroxyadenine and 8-hydroxyguanine (particularly mutagenic)

23
Q

What is p53 usually bound to

A

MDM2

24
Q

What causes p53 release from MDM2

A

stresses

25
Q

Activities of p53? (4)

A

apoptosis, senescence, growth arrest, DNA repair etc

26
Q

4 types of DNA repair?

A

DIRECT REVERSAL OF DNA DAMAGE:
BASE EXCISION REPAIR: (mainly apurinic and apyrimidinic damage)
NUCLEOTIDE EXCISION REPAIR: (mainly bulky DNA adducts)
DURING- OR POST-REPLICATION REPAIR:

27
Q

How does this type of DNA repair work: DIRECT REVERSAL OF DNA DAMAGE

A
  • Photolyase splits cyclobutane pyrimidine dimers

- Methyltransferases and alkyltransferases remove alkyl groups from bases

28
Q

How does this type of DNA repair work: BASE EXCISION REPAIR: (mainly apurinic and apyrimidinic damage)

A
  • DNA glycosylases cut out the damaged base
    apurinic/apyrimidinic endonucleases opens the strand up
  • A repair DNA polymerase fills the gap with a new replacement base and DNA ligase completes the repair
29
Q

How does this type of DNA repair work: NUCLEOTIDE EXCISION REPAIR: (mainly bulky DNA adducts)

A
  • A stretch of nucleotides either side of the damage are excised by endonuclease
  • Helicase unwinds the DNA and gets rid of the excised bit of DNA
  • Repair DNA polymerases fill the gap and DNA ligase completes the repair
30
Q

How does this type of DNA repair work: DURING- OR POST-REPLICATION REPAIR

A
  • Mismatch repair

- Recombinational repair of mistakes made when chromosomes swap over DNA

31
Q

Four fates of DNA damaged cell (4)

A

Return to normal
Apoptosis and cell death
Transcription and translation giving aberrant proteins
Carcinogenis

32
Q

5 stages of testing of carcinogenesis before human tests?

A
  1. We look for structural alerts i.e. look at the structure and see if it looks dangerous (e.g. if it looked like a previous carcinogen)
  2. Ames test- a bacterial gene mutation assay DNA in the bacteria has the same bases as human DNA- if it mutates/damages bacterial DNA it may do the same with human DNA
  3. In vitro mammalian cell assay- does it damage/mutate mammalian chromosomal DNA? (bacterial DNA is not chromosomal)
  4. In vivo mammalian assay Use animals to test the safety of it e.g. bone marrow micronucleus test
  5. Investigative in vivo mammalian assays- test for whether the chemical causes EPIGENETIC damage (as opposed to DNA damage)- let the animal live its life and watch for cancer
33
Q

Fundamental reasoning behind testing for mutations in pathogens?

A

DNA in the bacteria has the same bases as human DNA- if it mutates/damages bacterial DNA it may do the same with human DNA

34
Q

Explain the Ames test

A
  • Use bacteria that have been genetically mutated to require histidine to live
  • This mutation can be reversed- if it is reversed, the chemical can cause mutation and is carcinogenic
  • More DNA damage the chemical causes, the more colonies will grow on the agar (which has no histidine)
35
Q

Explain how to detect DNA damage in mammalian cells via chromosomal abberations

A
  • Incubate cells with DNA damaging chemical and karyotype or look at chromosomal structure
  • If the chromosome has been altered or damaged in any way, the chemical is carcinogenic/damages DNA
  • Slow test
36
Q

Explain how to detect DNA damage in mammalian cells via in vitro micronucleus assay

A
  • Much quicker than looking for chromosomal aberrations
  • Cells treated with chemical and allowed to divide (in test tube)
  • Binucleate cells are assessed for the presence of micronuclei- piece of chromosomal material which have broken off and no longer appear in the nucleus Chemicals that damage DNA can cause this
  • Can stain the kinetochore proteins to determine if chemical treatment caused clastgenicity (chromosomal breakage) or aneuploidy (chromosomal loss)
37
Q

What are micronuclei and what causes this

A

micronuclei- piece of chromosomal material which have broken off and no longer appear in the nucleus Chemicals that damage DNA can cause this

38
Q

Explain how to detect DNA damage in mammalian cells via BONE MARROW MICRONUCLEUS ASSAY IN MICE OR RATS:

A

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

39
Q

What base modifications do free radicals cause when damaging DNA (3)

A
  • Open rings of guanine and adenine
  • Form thymine and cytosine glycols
  • Hydroxylate purines to form 8-hydroxyadenine and 8-hydroxyguanine (particularly mutagenic)

Cancer Y2 (15 decks)

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