Session 10 - DNA Repair Flashcards
What are the 4 main stages in the cell cycle and what happens during these stages?
M Phase - Mitosis - Nuclear Division and Cytokinesis
G1 Phase - Cell content duplication
S Phase - DNA replication
G2 Phase - Double Check and repair
What is stage G0?
This is the stationary phase or quiescence. This is either temporary or permanently paused from replicating. It can (if pauses temporarily) be initiated by Growth Factors to return it to the cycle
What are where are the 3 checkpoints in the cell cycle and what controls this process?
Each checkpoint is done by CSKs/Cyclins. They are:
- Checkpoint in mitosis: Are all chromosomes properly attached to the mitotic spindle?
- G1 Checkpoint: Is environment favourable before S phase starts (DNA replication)?
- G2 Checkpoint: Is all DNA replicates? Is all DNA damage repaired?
Name some exogenous and endogenous sources of DNA damage.
Exogenous: Ionising Radiation, UV, Alkylating agents, Mutagenic chemicals, anti-cancer drugs, free radicals
Endogenous: Free radicals - mitochondria and white blood cells can cause damage, Replication errors
What may cause DNA replication stress (errors)?
- Mistakes with DNA polymerase - may cause mis-incorporation. DNA polymerase has an internal proofreading unit which reduces- mistakes to 1 in 10^9
- Topoisomerase - This removes supercoiling in front of DNA helicase but it cuts DNA in order to do this which can result in mistakes
- Fork slippage - Template or new strand slips out when there are lots of repeating bases
Explain how Huntington’s disease is brought about
Many CAG triplet repeats in HTT gene. During replication, fork slippage can occur leading to a trinucleotide expansion.
Leads to formation of mutant huntingtin proteins which aggregate in neurons
What are the 3 responses to DNA damage?
If damage is too big to repair: 1) Senescence 2) Apoptosis After DNA repair and cell cycle repair 3) Proliferation
What are the 3 base level DNA repair mechanisms?
- Base Excision Repair - Incorrect base is removed leaving base-less nucleotide. Which is then replaced with correct base.
- Nucleotide excision repair - Thymine dimer is detected and removed along with surrounding DNA (on same strand). New DNA replaced by polymerase. Ligase then joins phosphate backbone
- Mismatch repair - Similar to Nucleotide excision
What occurs during single strand break repair?
- Relatively simple
- Many mechanisms
- “damage” removed on one strand only
- Homology of other strand used to repair
- Not entirely error free but not error-prone either
What are the 2 types of double strand DNA repair?
1) Non-homologous end joining
2) Homologous-directed repair
What occurs during non-homologous end joining?
1- Broken ends recognised and protected
2- Complex formed and damaged ends removed
3- Broken ends ligated
This is very error prone as DNA is lost. Guaranteed Mutation. This is done if the machinery isn’t near for homology-directed. The risk is greater if it isn’t repaired
What are the stages in Homology-directed repair?
Homologous chromosome is used to extend the damaged strand until there is overlap and the ends bond through complimentary base pairing.
What is meant by the multistep cancer model?
This is where there is an accumulation of multiple mutations that lead from normal to pre-malignant to malignancy.
If there are mutations in DNA repair this stimulated carcinogenesis.
What is tumour heterogeneity?
This is a tumour which may have multiple cell lines. It won’t simply have a single mutation. Some may have mutated more, others less
What is differential sensitivity?
This is where chemotherapy is effective on a single type of tumour mutation. So in a heterogeneous tumour it only effects part of the tumour then the resistant tumour grows again.
