DNA Damage and Repair Flashcards
State some different types of DNA damage caused by carcinogens.
Base dimers and chemical cross-links Base hydroxylations Abasic sites Single strand breaks Double strand breaks DNA adducts
What are abasic sites?
During the repair process, the entire DNA base has been removed so the sugar backbone is maintained but we have removed the base from the mutagenic molecule
During replication, this missing base can cause problems
What are the implications of single strand breaks?
These are common and useful
Topoisomerase causes single strand breaks and it is involved in relaxing and unwinding the DNA before replication
What are the implications of double strand breaks?
These are NOT GOOD
The two strands have a tendency to drift apart when a double strand break occurs
There are repair mechanisms for dealing with this, but sometimes the DNA repair can go wrong and introduce DNA damage
What is the usual type of damage that is caused by chemicals?
DNA adducts
Why is DNA the target for many carcinogens?
Chemical carcinogens are usually metabolically activated and converted into electrophiles (they want electrons)
DNA is very electron rich
What are the consequences of bulky DNA adducts?
The electrophiles bind and form a covalent bond
The binding of these adducts causes problems, particularly during replication because it interferes with the ability of DNA polymerase to recognise the base (because of the bulky adduct)
What are the six types of Phase II reaction?
Glucuronidation Acetylation Sulphation Methylation Amino acid conjugation Glutathione conjugation
What are polycyclic aromatic hydrocarbons?
They are environmental pollutants formed from the combustion of fossil fuels and tobacco
Describe the two-step oxidation of benzo[a]pyrene.
B[a]P is a substrate for CYP450, which converts it to B[a]P-7,8-oxide (this is an electrophile)
The body has a defence mechanism – epoxide hydrolase converts the oxide to a dihydrodiol (B[a]P-7,8-dihydrodiol)
This is inactive
However, this dihydrodiol is also a substrate for CYP450, which converts it to another oxide (B[a]P-7,8-dihydrodiol-9,10-oxide)
This even more reactive than the previous oxide – it goes on to form DNA adducts
State two past components of dyestuff that are potent bladder carcinogens.
Benzidine and 2-naphthylamine
Explain the mechanism by which 2-naphthylamine is a bladder carcinogen.
2-naphthylamine is converted by CYP450 to a hydroxylamine derivative, which is reactive
In the liver, this is glucuronidated (thus inactivating it)
The inactive metabolite is excreted by the liver and then it goes to the bladder where it mixes with the urine
The ACIDITY of the urine causes hydrolysis of the glucuronides – this releases the hydroxylamine derivative, which forms a nitrenium ion
This is electrophilic so it leads to the formation of DNA adducts
What does UV radiation lead to the formation of?
Pyrimidine (thymine) dimers – adjacent pyrimidines can covalently link
What does ionising radiation generate?
Free radicals
Name 2 oxygen free radicals.
Superoxide radical (O2.) Hydroxyl radical (HO.)