DNA damage and repair Flashcards
What percentage of cancers are due to diet?
40-45%
What can damage DNA?
Chemicals: Dietary Lifestyle Environmental Occupation Medical Endogenous Radiation Ionising Solar Cosmic
Give an example of something endogenous that can damage DNA?
Mitochondria produce reactive oxygen species
What sort of DNA damage can carcinogens cause?
Base dimers and chemical cross-links
DNA adducts and alkylation
Base hydroxylations and abasic sites formed
Double and single strand breaks
What are base dimers and chemical cross links?
DNA molecules are being chemically linked up
What are base hydroxylations?
An oxidative reaction occurring on one of the DNA bases and this can cause problems as DNA might have to get repaired and during repair process, it could become mutated
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 mutagenic molecule- during replication, the missing base will cause problems
What are single strand breaks?
These are very common and useful
There are physiological enzymes that are responsible for making them
What is the role of topoisomerase?
It is involved in relaxing and unwinding of DNA- it works by chopping the strand of DNA and allowing the strand to unwind and we can gain access to the DNA as the strand is re-annealed
What are double strand breaks?
These are a bit of a disaster as after the double strand breaks thee is a tendency for the two bits of DNA to drift apart and this is intolerable -there are some DNA repair mechanisms that attempt to repair this but sometimes it can go wrong and introduce DNA damage
What generally causes DNA adducts and alkylation?
Chemicals- they tend to be metabolically activated into electrophiles and DNA is very rich in electrons because of all the nitrogens in bases
What happens in DNA adducts and alkylation?
Electrophiles bind to the DNA and form a covalent bond and the binding of a big bulky chemical to the DNA causes problems particularly during replication because the DNA polymerase runs along the strand and wants to figure out which base to put next but can’t because of the big chemical group
What are the two phases of mammalian metabolism?
Phase I:
Introduction or unmasking of functional groups that can be used in phase 2 (mainly cytochrome p450-mediated)
Phase 2: Conjugation of phase I functional groups with endogenous molecule to make it water soluble so it can be excreted in urine
What is the whole purpose of metabolism?
Take something that is lipophilic and make it more polar so that we can get rid of it
What are polycyclic aromatic hydrocarbons?
Common environmental pollutants (lot in smoke)
What is B[a]p?
Substrate for CYP450 which oxidises it to form an oxide (Benzo[a]pyrene-7,8-oxide)
What is the B[a]p oxide like?
It is reactive and wants to find electrons
What is the body’s defence mechanism against B[a]p oxide and other polycyclic aromatic hydrocarbon oxides?
Epoxide hydroxylase cleaves the three membered strained ring of the oxide to form a dihydrodiol- not toxic
What happens to the dihydrodiol that is formed?
It is unfortunately a substrate for p450 as well so p450 converts this non-toxic metabolite into another oxide which is very reactive and desperate to find some electrons to react with and best source of electrons is DNA so DNA adducts are formed
What are 2-napthylamine and benzidine?
Part component of dye stuffs and potent bladder carcinogens
How do polycyclic aromatic hydrocarbons cause cancer in many parts of the body?
P450 is involved in its activation and found in lots of different tissues
What do aflatoxins primarily target?
The liver because it is mainly activated by p450 that is found in the liver
What is 2-naphthylamine a substrate for?
CYP450 which converts the amino group to form a hydroxylamine (N-hydroxy-2-naphthylamine)- they are reactive
What happens to the reactive hydroxylamine in the liver?
It is glucuronidated (detoxified) so chemical is activated and inactivated
What happens to the glucoronide in the urine?
Urine is acidic so glucuronide is hydrolysed and this releases the hydroxyl amine derivative which in acidic conditions rearranges to form a positively charged nitrogen (nitrenium ion)
What does the nitrenium ion do?
It is an electqrophil which then goes and binds to DNA and forms adducts- bladder isn’t as capable at detoxifying the hydroxyl amine derivative as the liver
What can UV radiation lead to the formation of?
Pyrimidine dimers- under UV radiation they can covalently link
What is the main type of cancer that UV radiation causes?
Skin cancer