7. DNA damage and repair Flashcards
With which type of cancer is ethanol particularly associated?
Breast
Recall an example of an occupational carcinogen
Tar smoke in laying roads
Recall 2 medical examples of carcinogens
X Rays
Chemotherapy
Recall the 4 main mechanisms of DNA damage
- DNA adducts
- Base dimers + chemical crosslinks
- Strand breaks
- Base hydroxylation
What is the most common class of environmental pollutants? Recall how they are produced
Polycyclic aromatic hydrocarbons - produced by burning fossil fuels + tobacco
Summarise the normal metabolism of B[a]P
2 step oxidation:
- CYP450 –> epoxide
- Epoxide hydrolase –> 2 unreactive alcohol molecules
Recall where the metabolism of B[a]P most frequently is dysfunctional
Production of diol epoxide = hugely reactive with DNA to produce adduct
Why are unstable products of metabolism attracted to DNA?
Since it is nitrogenous = good source of electrons to stabilise molecule by binding with it
Where is faulty B[a]P metabolism most likely to cause cancer?
Anywhere in body
Recall three examples of polycyclic aromatic hydrocarbons
- Benzo[a]pyrene
- Aflatoxin B1
- 2-napthylamine
How is aflatoxin B1 formed and where is it most commonly found?
Aspergillus flavus mould
Poorly stored grains and peanuts
Where is a DNA adduct caused by aflatoxin B1 most likely to cause cancer?
Liver
Where is a DNA adduct caused by 2-napthylamine most likely to cause cancer?
Bladder
Recall the normal metabolism of 2-napthylamine
- CYP1A2 –> reactive metabolite
2. Detoxified by glucuronidation (sugar addition)
Why is 2-napthylamine particularly associated with bladder cancer?
Acidic urine pH removes the sugar from the metabolite of 2-napthylamine, thus toxifying it
How does solar radiation cause damage?
UV light reacts with thymine to produce a crosslink, when the cell tries to repair this it introduces a mutation
How does ionising radiation lead to DNA damage?
Generates superoxide/ hydroxyl free radicals –> very reactive with DNA
What are the consequences of oxygen radicals?
- Double and single strand breaks
- Apurinic and apyrimidinic sites
- Base modification
What is the normal function of p53
TSG that detects and responds to DNA damage:
Mild damage –> repair, overwhelming damage –> apoptosis
How is P53 activated?
Released from MDM2
Recall the 4 main mechanisms for DNA repair
- Direct reversal of DNA damage
- Base excision repair
- Nucleotide excision repair
- During or post-replication repair
Give an example of direct reversal of DNA damage
Pyrimidine dimers produced by UVB exposure can be fixed by a family of enzymes called photolyases
What are the main enzymes involved in identifying sites for base-excision repair
DNA glycoylases
Apurinic/ apyrimidinic endonucleases
Summarise the mechanism of nucleotide excision repair
XP proteins assemble at damage site and stretch of nucleotides either side of adduct is cut out, repair polymerases fill gap
