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
What are the DNA repair mechanisms?
- DNA polymerase exonuclease (during replication)
- Base-excision repair (single strand and deanimation)
- Nucleotide excision repair (bulky adducts)
- Mismatch repair
- Non-homologous end joining
- Homologous directed repair
How is a double strand break fixed?
Non-homologous: (X)
- Break recognised by proteins
- KU70/80 protein form ring around ends to protect ends
- DNA-PKcs trim nucleotides off end
- DNA ligase fuses strands back together
- Mutation as loss of nucleotides
Homologous (Y)
- Exonucleases cut strands to form single strands
- Single strands complementary to non sister chromatids so invade the double helix from both directions forming holiday junction
- Non-sister chromatids act as a template and DNA polymerase and ligase work together
Why do we have to do HR and NHR if it causes mutations?
- DNA not protected by telomeres otherwise and so they can’t undergo mitosis/meiosis
What is intratumour heterogeneity?
Tumour has subclones due to different mutations, mosaicism
What can cause carcinogenesis?
- DNA Replication Stress
- If there is a fault in the DNA damage response so cells not killed when mutation
What is the multi-step cancer model?
Mutiple mutations have to occur for a cell to become malignant. DNA repair mechanisms can usually prevent it
What is the issue with chemotherapy?
- Can induce mutations as radiation and selection pressure
- Forms heterogenous tumour (chemo may kill one subclone but allow survival of the fittest of another)
What are synthetic lethality strategies?
- Normal cells may have two genes that aid cell survival
- Cancer cell may have one of those genes not working, e.g gene A
- Produce a drug that targets gene B so cancer cells die as they have no gene A but normal cells survive as they have gene B for back up
What is an example of a synthetic lethality strategy?
PARP inhibitor for breast cancer treatment
- Breast cancer cells not good at repairing double strand break but normal cells can
- Inhibiting PARP causes lots of DSB’s
- Cancer can’t fix these so apoptosis but normal human cells can
What is xeroderma pigmentosa?
Autosomal recessive disorder where you have a decreased ability to repair DNA damage, e.g damage done by UV light
What cells are in G0 for life?
- Neurones
- RBC
- Skeletal muscle
- Retinal cells
What do telomeres do and what does telomerase do?
Telomeres: Protect chromosomes from damage and prevent chromosomes fusing together
Telomerase: A reverse transcriptase that prevents telomeres shortnening when primers are formed on telomeres
