DNA repair & cancer

Question 1

Name 5 exogenous sources of DNA damage

Answer 1

• Ionising radiation
• Alkylating agents
• Mutagenic chemicals
• Anti-cancer drugs
• Free radicals

Question 2

What is DNA replication stress?

Answer 2

Inefficient replication that leads to replication fork slowing, stalking and/or breakage

Question 3

What is a replication fork?

Answer 3

Structure that forms within the long helical DNA during replication

Question 4

What replication errors can occur (3 things)?

Answer 4

• Misincorporation of base pairs and proofreading
• Hindrance of replication fork progression
• Repetitive DNA sequences can lead to fork slippage

Question 5

Endogenous responses to DNA damage (4 things)

Answer 5

• Cell cycle transitions
• Apoptosis
• Transcription
• DNA repair

Question 6

What facilitates the DNA damage response (4 things)?

Answer 6

• Signals
• Sensors
• Transducers
• Effectors

Question 7

3 types of single strand break repair

Answer 7

• Base excision repair
• Nucleotide excision repair
• Mismatch repair

Question 8

Base excision repair (4 things)

Answer 8

• 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

Question 9

Nucleotide excision repair (4 things)

Answer 9

• 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

Question 10

Mismatch repair (4 things)

Answer 10

• 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

Question 11

3 types of double strand break repair

Answer 11

• Non-homologous end joining
• Homology-directed repair
• Holliday junction resolution

Question 12

Non-homologous end joining (4 things)

Answer 12

• 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

Question 13

Homology-directed repair (4 things)

Answer 13

• 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

Question 14

How do mutations lead to cancer?

Answer 14

They accumulate over time until a threshold is passed- takes multiple to produce cancer

Question 15

Lynch syndrome key points (4 things)

Answer 15

• Caused by mutations in mismatch repair genes
• Autosomal dominant inheritance
• High risk of colorectal, endometrial, gastric & ovarian cancer
• Treated by surgery in many cases

Question 16

How does cancer evolve?

Answer 16

Via intertumour and intratumour (different cell types in a tumour) heterogeneity

Question 17

How does heterogeneity affect cancer treatment (2 things)?

Answer 17

• It can limit the ability of chemotherapy
• Can have chemotherapy resistant tumours

Question 18

What are synthetic lethality strategies?

Answer 18

Can make use of redundancy in genetic pathways so drugs target cancer cells but not normal cells

Question 19

Ataxia telangiectasia key points (4 things)

Answer 19

• Failure of homology directed repair
• Autosomal recessive inheritance (co-sanguinity)
• Patients are sensitive to UV damage
• Currently no treatments