Genes and environment in cancer development Flashcards
What is a DNA mutation?
- Damaged DNA that is not properly repaired
> Damaged DNA that is not properly repaired leads to mutations that activate oncogenes or inactivate tumour suppressor genes.
What are the 2 ways DNA can be damaged.
1) exogenous factors from the environment
2) endogenous factors from cellular metabolism and DNA replication errors
Give 2 examples of environmental induced DNA damage?
> Cell genomes are under occasional attack from exogenous mutagens
a) UV radiation: UV-A and UV-B
b) Chemical exposure, e.g. cigarette smoke
How does UV-A/UV-B cause DNA damage?
- Generates 2 major types of DNA lesions (sections of DNA molecule containing primary damaged site.)
> UV forms dimers at dipyrimidine sites
Cyclobutane pyrimidine dimer (CPD) +
Pyrimidine (6-4) pyrimidone photoproduct (6-4PP).
= Very stable + persists for extended periods unless removed by DNA repair enzymes
What does CPDs and 6-4PPs cause in a DNA strand?
> Which lesion causes more damage?
- Convex bend or kink in one strand of DNA (intrastrand crosslinks) therefore distort DNA structure. = prevents transcription and replication
> 6-4PP is more DNA distorting (44° bend of DNA helix) than CPD (9° helix bend).
Explain how the following image represents UV induced mutagenesis.
1- Cyclobutane pyrimidine dimer (CPD) and 6-4 photoproduct (6-4PP) lesions are UV-induced dimers formed at dipyrimidine sites
2- CPDs are generated by UV from simulated sunlight 6 times more frequently than 6-4PPs.
3- UVA and UVB irradiation generate CPD and 6-4PP DNA lesions.
> Deamination may occur at CPDs.
4- 1st DNA replication after lesion formation, correct or incorrect nucleotides are incorporated opposite of the lesion via different mechanisms including misincorporation and error-free and error-prone translesion synthesis (TLS).
5- 2nd DNA replication, complementary nucleotides are incorporated opposite of the correct or incorrect nucleotides that were from the first round. This results in mutation fixation.
6- Due to the abundance and slow repair of CPDs, the resulting C > T mutations are the most prevalent
> UV signature mutations
*Direct replication of DNA damage is termed translesion synthesis(TLS).
What Chemical compound in cigarette causes DNA damage? > Give an example.
- Polycyclic aromatic hydrocarbons > Benzo[a]pyrene
Benzo[a]pyrene is a procarcinongen… name the ultimate carcinogen.
> How is ultimate carcinogen formed?
- Benzo[a]pyrenediolepoxide (BPDE)
> Procarcinogens are chemically inert precursors that are metabolically converted into highly reactive carcinogens.
Benzo[a]pyrene is not itself carcinogenic. It undergoes two sequential oxidation reactions mediated by cytochrome P450 enzymes (CYP1A1), which results in benzo[a]pyrenediol epoxide (BPDE), the carcinogenic metabolite that can form a covalent DNA adduct.
Explain how The ultimate carcinogen Benzo[a]pyrenediol epoxide (BPDE) causes DNA damage?
- Attack DNA molecules directly through their ability to form covalent bonds with various bases.
- BPDE leads to guanine adducts in DNA
> The chemical entity formed after reaction of a carcinogen is a DNA adducts.
The chemically reactive epoxide group of benzo[a]pyrenediolepoxide (BPDE) can attack a number of chemical sites in DNA to form DNA adducts.
- Name these sites.
- Extracyclic amine of guanine (shown here),
- Two ring nitrogens
- O6 of this base.
What does the guanine-BPDE adduct cause in DNA?
-
Mispairing of a G base with an A base in DNA.
> When this DNA is replicated, the new copy has a T where the old copy had a G (translesion synthesis (TLS)), called a G-to-T transversion.
What gene is commonly mutated in lung cancer?
> What is significant about G>T transversions in lung cancer?
- Tumor surpressor gene P53
> p53 mutations in lung cancer are different from those in other cancers and that an excess of G-to-T transversions is characteristic for lung cancers.
How does cellular metabolism cause DNA damage?
- Spontaneous oxidative DNA damage caused by free radicals and other reactive oxygen species (ROS)
-> During Oxidation
-> In the mitochondria a series of reactions occur that generate variety of intermediates = Reactive oxygen species) as oxygen is progressively reduced to water.
What do Reactive oxygen species (ROS) induce to cause dna damage?
1- Single- and double-strand breaks of DNA double helix
2- Induces oxidation of deoxyguanosine to the nucleotide 8-oxo-deoxyguanosine (8-oxo-dG).
How does the formation of 8-oxo-deoxyguanosine ( (8-oxo-dG) create a danger of mutations?
1- One conformation of this altered base can readily pair with A.
2- This mispairing of bases during DNA replication can lead, in turn, to the replacement of a G:C base pair, via G:A pairing, to a T:A base pair.
3- Such a G →T replacement of a purine by a pyrimidine (or the opposite) is often termed a transversion.
How do errors made during DNA replication cause DNA damage?
1- Polymerase enzymes sometimes inserting the wrong nucleotide or too many or too few nucleotides into a sequence.
= Induces mismatched pair = Wobble
> DNA double helix is flexible , able to accommodate slightly misshaped pairings.
2- Strand slippage
> A DNA strand may loop out, resulting in the addition or deletion of a nucleotide
Explain why the following 2 wobbles have formed?
- A shift in the position of nucleotides causes a wobble between a normal thymine and normal guanine.
- An additional proton on adenine causes a wobble in an adenine-cytosine base-pair.
(DNA double helix is flexible and able to accommodate slightly misshaped pairings.)
What are the 2 ways Double stranded breaks can be repaired?
- Homologous recombination (HR) and
- Non-homologous end joining (NHEJ).
Explain what Cancer susceptibility gene mutation is?
> Give an example.
- Term that describes mutations in certain genes that may increase a person’s risk of some types of cancer.
- Usually inherited (passed from parent to child) and may be seen within families.
> Certain mutations in the BRCA1 or BRCA2 gene has higher than normal risks of developing breast cancer and ovarian cancer at younger age.
Why does BRCA1/2 cause cancer?
- BRCA1 and BRCA2 participates in double-strand break repair by homologous recombination (HR)
What are tumour promoters? Give 2 examples.
- Substances that accelerate cell turnover so that genetically damaged cells multiply more rapidly and have greater likelihood of acquiring additional mutations needed for malignant transformation.
e.g. Hormones and growth factors from adipocytes
Give 2 explanations on why being overweight can cause cancer?
1- Fat cells make extra growth factors + hormones > Tell cells in our body to divide more often > Increases chance cancer cells being produced > which can divide and cause tumour
2- Cells overloaded with lipids rapidly outgrow oxygen supply leading to cell death and inflammation = tissues turn bad
