DNA repair & cancer Flashcards
Name 5 exogenous sources of DNA damage
- Ionising radiation
- Alkylating agents
- Mutagenic chemicals
- Anti-cancer drugs
- Free radicals
What is DNA replication stress?
Inefficient replication that leads to replication fork slowing, stalking and/or breakage
What is a replication fork?
Structure that forms within the long helical DNA during replication
What replication errors can occur (3 things)?
- Misincorporation of base pairs and proofreading
- Hindrance of replication fork progression
- Repetitive DNA sequences can lead to fork slippage
Endogenous responses to DNA damage (4 things)
- Cell cycle transitions
- Apoptosis
- Transcription
- DNA repair
What facilitates the DNA damage response (4 things)?
- Signals
- Sensors
- Transducers
- Effectors
3 types of single strand break repair
- Base excision repair
- Nucleotide excision repair
- Mismatch repair
Base excision repair (4 things)
- Deamination changes a base to a different one
- It’s detected and removed, leaving a baseless nucleotide
- Nucleotide removed leaving a small hole in backbone
- Hole filled with right base by a DNA polymerase and sealed by a ligase
Nucleotide excision repair (4 things)
- UV radiation produces a base dimer
- Once detected, surrounding DNA is opened to form a bubble
- Enzymes cut damaged region out of bubble
- A DNA polymerase replaces excised DNA and a ligase seals backbone
Mismatch repair (4 things)
- Mismatch detected in newly synthesised DNA
- New strand cut and mismatched nucleotide and its neighbours removed
- Missing patch replaced with correct nucleotides by a DNA polymerase
- A DNA ligase seals the gap in backbone
3 types of double strand break repair
- Non-homologous end joining
- Homology-directed repair
- Holliday junction resolution
Non-homologous end joining (4 things)
- Broken ends bound by proteins
- A complex is bound followed by trimming of excess bp involving certain proteins
- Ligase repairs break
- New DNA may not be exact copy of original
Homology-directed repair (4 things)
- DNA either side of break is resected by a protein complex
- Allows a heteroduplex to form
- A displacement loop moves along DNA, making a complementary strand
- Polymerases and ligases repair break as newly synthesised DNA is captured by original template
How do mutations lead to cancer?
They accumulate over time until a threshold is passed- takes multiple to produce cancer
Lynch syndrome key points (4 things)
- Caused by mutations in mismatch repair genes
- Autosomal dominant inheritance
- High risk of colorectal, endometrial, gastric & ovarian cancer
- Treated by surgery in many cases
How does cancer evolve?
Via intertumour and intratumour (different cell types in a tumour) heterogeneity
How does heterogeneity affect cancer treatment (2 things)?
- It can limit the ability of chemotherapy
- Can have chemotherapy resistant tumours
What are synthetic lethality strategies?
Can make use of redundancy in genetic pathways so drugs target cancer cells but not normal cells
Ataxia telangiectasia key points (4 things)
- Failure of homology directed repair
- Autosomal recessive inheritance (co-sanguinity)
- Patients are sensitive to UV damage
- Currently no treatments
