3 - DNA Repair And Cancer Flashcards
What can cause mutagenesis?
- *EXOGENOUS SOURCES:**
- Free radicals
- Ionising radiation (food, x-rays, background)
- Anti-cancer drugs
- Mutagenic agents
ENDOGENOUS SOURCES:
- Replication erros
- Transposable elements
- Free radicals
SPONTANEOUSLY
Where do free radicals come from?
- Mitochondria
- Smoking
- WBC
- UV
- Radiation
Can mutations be repaired?
Yes, by DNA repair mechanisms but sometimes these mechanisms fail so there is a mutation
What is DNA replication stress?
Inefficient replication that leads to replication fork slowing, stalling and or breakage. Leads to mutations
- Replication machinery defects
- Fork progression hinderance
- Defects in reponse pathways
What is a mosaic karyotype?
47,+21/46,N
Due to non-disjunction occur in first few mitotic divisions
Why can replication machinery defects lead to mutations?
- DNA polymerase may incorporate wrong base accidentally
- Exonuclease domain misfunctional so can’t remove it
- Increased mutation rate
What factors can slow down fork progression?
- DNA lesions (dimers due to UV)
- Transcription occuring
- Looping
- Repetitive sequences
Why do dimers result in mutation?
Have to wait for DNA damage response to occur before replication can continue.
Therefore replication has slowed so DNA replication stress
Why do nucleotide repeats lead to mutations?
FORK SLIPPAGE
Backward leads to insertion
Forward leads to deletion
What is Huntingtons disease?
- Trinucleotide repeat disorder of CAG
- Normally it is 6-39 repeats
- 35-121 is Huntingtons
- The more repeats you have the earlier the onset
- Autosomal dominant
- Mutant misfolded protein accumulates in neurons so neurodegenerative disease (mainly basal ganglia)
What is the function of the normal protein for the HTT (huntingtons) gene?
Unknown
What is the mechanism behind HD?
- Backward fork slippage of trinucleotides during DNA replication
- Loops straighten out for second replication so new DNA is three nucleotides longer, continues
What is the DNA damage response pathway?
- Sensor will detect DNA damge
- Send signal to transducers
- Sends signals to effectors
Why are there cell cycle checkpoints?
Temporary arrest to allow DNA repair
What is the issue with a cell that undergoes senescence?
- It enters G0 as it has mutations but can still function
- May pick up more mutations and reenter G1, which could lead to uncontrollable division