Causes and types of DNA Damage Flashcards
(28 cards)
What are external causes of DNA damage?
- environmental
- radiation
- chemical
What are the internal causes of DNA damage?
- cellular metabolism
- enzymatic processes
Mutations in critical genes involved in what processes can cause disease and tumour development?
- cell metabolism
- cell function
- cell cycle
What two types of mutations are there?
Germline mutations and somatic mutations
What is a small scale mutation?
This is a point mutation that can be an insertion or deletion. They can be silent, nonsense or missense mutations and can affect protein translation.
What is a large scale mutation?
These are gene amplifications, deletions or re-arrangments that cause alterations at the chromosomal level.
Oxidative stress
The formation of reactive oxygen species like hydroxyl radicals due to ionising radiation, UV or enzymatic reactions that cause the guanine to be converted to 8-oxo-G. 8-oxo-G pairs with A and causes a GC—>TA mutation.
What is 8-oxo-G a marker of?
- Oxidative stress
- Carcinogenesis
- Disease states
What diseases can oxidative stress induced DNA damage cause?
- rheumatoid arthritis
- Alzheimer’s disease
- AIDS
- Huntington’s Disease
- Cardiovascular diseases
- Diabetes
- COPD
- Inflammatory Bowel Disease
Alkylation of DNA bases
Cytotoxic, mutagenic or neutral lesions caused by exogenously or endogenously produced alkylation reagents mainly targeting exocyclic nitrogens and oxygens or ring nitrogens.
What is the most common form of alkylation and what are the common products?
Methylation is the most common and the main products seems are N7-methylguanine, N3-methyladenine and O6-methylguanine.
What kind of lesions do O-alkylations cause?
Mutagenic/harmful lesions
What type of lesions do N-alkylations cause?
Cytotoxic lesions that block replication, interrupt transcription or signal apoptosis.
Deamination of bases
This is the removal of the amine group from the DNA base caused by spontaneous hydrolysis, nitrosative stress or deaminases.
What are the main targets and the products od deamination.
- Guanine to xanthine causing 2 bonds with cytosine where there should be three.
- Cytosine to Uracil (RNA base, should not be in DNA) causing paring with adenine (2 bonds).
- Adenosine to hypo-xanthine causing pairing with cytosine (3 bonds).
- 5-methylcytosine to thymine resulting in a GC>TA mutation.
Loss of DNA Bases
The removal of a DNA base resulting in an abasic AP site caused by spontaneous depurination, DNA damage or BER intermediates leading to complete deletion after replication.
What are the consequences of loss of DNA bases
- Replication fork stalling
- Cells copy DNA containing unrepaired damage.
- Mutations during replication.
Bulky Adduct Formation
The covalent bonding of biologically reactive compounds like benzo[a]pyrene to DNA bases causing a reaction with guanine leading to G>T mutation.
What is benzo[a]pyrene found in and why is it so dangerous?
It is found in coal tar, tobacco smoke and grilled foods. It I dangerous because it is a procarcinogen.
Is benzo[a]pyrene reactive on its own?
No.
How does benzo[a]pyrene become reactive?
CYC1A1, CYP1B1 and epoxy-hydrolyses adds it to DNA.
Crosslinking of DNA
intra or inter-strand double or single covalent bonds form between DNA bases which interferes with DNA replication, translation and triggers cell death.
What causes cross linking of DNA and where does it most commonly act?
Non-ionizing radiation like UV light affecting pyrimidine residues specifically two thymines.
What major pathology do crosslink induced pyrimidine dimers cause?
Melanomas.
