Genes and environment in cancer development Flashcards
(27 cards)
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.
What is replication stress?
- A number of conditions, including those leading to high levels of DNA damage, may interfere with DNA replication and hamper its progression.
-
DNA synthesis slow down and/or replication fork stalling and is the primary cause of genome instability.
> A feature of pre-cancerous and cancerous stress.
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.)
To maintain the integrity of their genomes, cells have therefore had to evolve mechanisms to repair damaged DNA.
- Name the two general classes these mechanisms of DNA can be divided into?
1- Direct reversal (DR) of the chemical reaction responsible for DNA damage
2- Removal of the damaged bases followed by their replacement with newly synthesized DNA (excision repair).
What is excision repair?
- General means of repairing a wide variety of chemical alterations to DNA.
> Damaged DNA is recognized and removed, either as free bases or as nucleotides.
> Gap is then filled in by synthesis of a new DNA strand, using the undamaged complementary strand as a template.
What are the 3 types of excision repair?
- base-excision repair (BER)
- nucleotide-excision repair (NER)
- mismatch repair (MMR)
What DNA repair mechanism is needed for the following DNA damaging agents?
1- DNA replication stress > Base mismatch (insertions/deletions)
2- Oxygen radicals > ss DNA breaks + 8-oxo-deoxyguanosine
3- Polyaromatic hydrocarbons > DNA adducts
4- UV light > CPDs/6-4PPs
1- Missmatch repair
2- Base-excision repair
3- Nucleotide excision repair
4- Nucleotide excision repair
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.
