Session 6 ILO's - DNA repair and cancer Flashcards
Describe Ataxia Telangiectasia (4)
- Rare neurodegenerative disease (degeneration of the nervous system, specifically the neurones in your brain) that causes severe disability
- Damage to the cerebellum causes difficulty with movement and coordination
- Heightened radiation sensitivity and weakened immune system
- DNA repair is disrupted, so increased risk of cancer
Explain and describe the DNA damage response
- During the normal course of the life, DNA can be damaged by lots of endogenous and exogenous agents
- Damage to DNA is usually sensed by the cell and repaired using a set of repair mechanisms
- This will restore the DNA to it’s healthy/normal state
- In some cases, if the damage to DNA is too big or if the DNA repair mechanism is faulty, a mutation can occur
- This can be propagated in cells throughout the germline or in daughter cells, leading to the expression of a disease
Name sources of DNA damage
Exogenous (external) sources of DNA damage :
Ionising radiation
UV light
Mutagenic chemicals
Anti-cancer drugs
Alkylating agents
Free radicals
Endogenous (internal) sources of DNA damage:
Free radicals
Replication errors
Compare single and double strand DNA breaks
Single:
- Only one side of the DNA moleucule is damaged
Double:
- Both sides of the DNA molucule is damaged
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Describe the variety of exogenous and endogenous factors that can cause DNA damage
Exogenous (external) sources of DNA damage :
Ionising radiation
UV light
Mutagenic chemicals
Anti-cancer drugs
Alkylating agents
Free radicals
Endogenous (internal) sources of DNA damage:
Free radicals
DNA Replication errors
Describe the general outline of the different phases of the eukaryotic cell cycle, including G0
G1 = Growth 1 - where the cell content duplicates itself
S = DNA replication - when the DNA replication occurs
G2 = Growth 2 - where the cell is double checked and repaired
M = Mitosis/Meiosis - where cell division/replication occurs
G0 = resting phase
G0 phase comes off G1 stage and cells in this phase are not immediately preparing to divide. G0 can be a temporary or permanent phase depending on the cell type & properties
EXAMPLE: Some cells enter G0 temporarily until an external signal triggers the onset of G1 e.g. liver cells Whereas cells that never or rarely divide, such as mature cardiac muscle and nerve cells, remain in G0 permanently.
Appreciate the complexity of cell cycle control and the consequence of loss of control
Give examples of types of DNA damage
- Single strand damage/breaks
- Double strand damage/breaks
- Deamination
- The formation of dimers between different nucleotides
- Crosslinking between strands
- The linking of intercalating agents.
- Replication stress, for example when the replication
fork is slowed down, or fork slippage occurs – DNA that contains many repetitive sequence is harder to copy accurately and in some cases this can trigger the formation of protein aggregates leading to disease.
- Base change (apurinic site)
- Dimers (additional chemical structures)
- Interstrand cross links
4.Mismatch/insertion/deletion
- Misincorperation of base pairs and proofreading errors
ASK ABOUT THESE
Describe in general terms what is meant by replication stress and the differentiat ways it can be caused
Replication stress is the inefficient DNA replication that leads to replication fork slowing, stalling and/or breaking
- Replication machinery defects EXAMPLE: DNA polymerase mis-incorporation
- (factors hindering replication fork progression) Replication fork progression hindrance EXAMPLE: fork slippage (backwards or forwards)
- Defects in response pathways EXAMPLE: regulation of origin firing, helicases
Outline and explain how fork slippage cause mutations
- Repetitive sequence within the DNA sequence can lead to fork slippage, meaning you copy the wrong number of these repetitive sequences
- E.g fork slippage can lead to expansion of trinucleotide repeats (common in diseases like Huntington’s disease and spinocerebellar ataxia, fragile X syndrome
- The DNA molecule compares repeats of 3 base pairs, and large numbers of these over time, (e.g AAAAAAA, large numbers of the base pair A found in one stretch of DNA
- The DNA polymerase finds it hard to accurately copy these, and in some cases will incorporate extra base pairs, leading to slippage and an expansion in the size of the gene
Describe the 2 scenarios in the image
- Resulting in insertion
- Resulting in deletion
Compare and describe in general terms of number of single strand breaks repair mechanism and double strand repair mechanisms
Appreciate the potental consequences of error-prone double strand repair
Describe the complex relationship between mutations, DNA repair and cancer
DNA repair factors can repair mutations, which helps to prevent cancer from forming (stops pre-malignant cells) - however defects in DNA repair factors stimulate carcinogenesis. There are thousands of different DNA repair factors, which makes it more complex!
Using synthetic lethality strategies, you can use the cell’s DNA repair factors against it!
Compare single- and double stranded DNA breaks
Explain different DNA repair mechanisms – basepair and nucleotide excision,
mismatch repair, non-homologous end joining and homologous recombination
- Base-excision repair
Where the base has been converted, the wrong base is detected and removed, the sugar phosphate is removed and the new, correct nucleotide is added in - Nucleotide-excision repair
Where there is a dimer (double base addition), the surrounding DNA is opened to form a bubble. The bubble is cut out, new undamaged DNA is synthesised (5’ -> 3’) and is inserted and fused by ligase - Mismatch repair
A mismatch is identified in newly synthesised DNA and is cut out by exonuclease activity (including it’s neighbours), new undamaged DNA is synthesised (5’ -> 3’) and is inserted and fused by ligase - Non homologous
- Homologous
