Cancer 5: DNA damage and repair Flashcards
What can cause base modification?
- deamination
- chemical modification
- photodamage
How does deamination work with DNA?
-primary amino groups of nucleic acids are unstable and converted to ketogroups
What are examples of deamination reactions?
adenine to hypoxanthine
guanine to xanthine
5-methyl cytosine to thymine
Give an example of how chemical modification can occur
by hyper-reactive oxygen species which can be generated during normal oxidative metabolism or ionizing radiation
What happen during photodamage?
UV light is absorbed by nucleic acid bases and the influx of energy can induce chemical changes
List some types of DNA damage? (4)
- ruck
- gap
- thymine dimer
- base pair mismatch
What can be a source of CARCINOGENS that contribute to DNA damage?
- dietary
- environmental
- lifestyle
- occupational
- medical
- endogenous
What sources of RADIATION lead to DNA damage?
- ionizing
- solar
- cosmic
List 4 types of DNA damage by carcinogens
- DNA adducts and alkylation
- base dimers and chemical cross-links
- base hydroxylation and abasic sites formed
- double and single strand breaks
What are the 2 phases of mammalian metabolism?
phase I adds functional groups mainly via cytochrome p450
phase II conjugates the functional groups so it becomes water soluble
What is cytochrome p450 responsible for?
oxidising chemicals
How are polycyclic aromatic hydrocarbons formed?
- combustion of tobacco
- combustion of fossil fuels
they form carcinogens
What can arise from the epoxidation of aflatoxin B1?
human liver carcinogen
What can arise from the metabolism of 2-naphthylamine?
human bladder carcinogen
What type of cancer can UV radiation lead to?
-skin
can lead to the formation of pyrimidine dimers
How does ionising radiation cause damage?
-generates free radicals
super oxide radical and hydroxyl radical which then seek out electron-rich DNA
What type of DNA damage does oxygen free radical attack cause?
- double and single strand breaks
- base modifications
- apurinic and apyramidic sites
What is p53?
a CRUTIAL tumour suppressor gene
How does p53 work with cellular stress?
it is usually paired with MDM2 which keeps it inactive
when it is released it forms an active dimer
- under MILD physiological stress it activates proteins that help repair the problem
- under HIGH physiological stress it triggers an apoptotic pathway
List 4 types of DNA repair?
- direct reversal of DNA damage
- Base excision repair
- nucleotide excision repair
- during or post replication repair
How is DNA mismatch repair done?
- it enlists the aid of enzymes involved in base-excision repair and nucleotide-excision repair
- recognition requires proteins including one encoded by MSH2
- cutting of the mismatch requires proteins, one encoded by MLH1
How is direct DNA repair carried out?
- photolyases repair thymine dimers
- MGMT directly reverses simple alkylation adducts
How does base excision repair work?
mainly targets apurines and apyrimidines
DNA-glycosylases and endonucleases repair this
DNA polymerase fills in the gap left by this base and then DNA ligase completes the repair
How does nucleotide excision repair work?
for bulky DNA adducts
-Xeroderma pigmentosum proteins assemble at the site of damage
DNA polymerase fills int he gap and ligase completes the repair
