Lec 3 DNA Repair and Cancer Flashcards
what are the two types of DNA damage?
single and double stranded damage
what is done when DNA is damaged?
we undergo DNA repair mechanisms
if this fails we get mutations that can go on to cause cancer
there are lots of external and internal sources of DNA damage. give some examples
external - Ionising radiation,UV light, alkylating agents, free radicals, mutagenic chemicals, anti-cancer drugs
Internal - Free radicals, Replication errors
give the key fact you need to know about DNA damage
that there are lots of different ways that DNA can be damaged, and lots of different mechanisms to fix these different types of damage
What is DNA replication stress?
Inefficient replication can lead to replication fork slowing, stalling or breakage
Give two examples of DNA replication stress
Misincorporation - DNA polymerase adds an incorrect base. DNA exoneuclease 3’ to 5’ (opposite) will remove the mismatch.
DNA poly adds the correct base
Fork Slippage - Repetitive DNA can give fork slippage
where the new strand ends up with 1 more or 1 less base.
give an example of a fork slippage condition.
Huntingtons disease - trinucleotide repeat disorder
CAG fork slippage, so too many CAG repeates
it codes for polyglutamene which also has too many repeats, the excess polyglutamine means the protein cannot fold up properly and builds up on the neuron, leading to neuron degeneration
it is autosomal dominant and progressive, late onset
What is the DNA damage response system?
a signal of the issue is released ( the issue itself)
sensors notice the issue, and pass it on to transudcers
they say something is wrong!!!!
the effectors happen - senescence, apoptosis, DNA Damage repair, Transcription, cell cycle transitions to check for issues.
what is senescence?
a permanent arrest of the cell cycle
more mutations can cause further problems
why do we have cell cycle check points, where are they?
they are after G1 is , after G2 - is DNA damage repaired
and a mitosis checkpoint.
temporary arrest to allow DNA repair
give 3 examples of single strand repair mechanisms
Base excision repair
a demaination converts cytosine to uracil
uracil detected and removed
baseless nucleotide is removed
hole in the DNA backbone is repaired by DNA polymerase and sealed by ligase
Nucleotide excision UV radiation produces a thymine dimer a DNA bubble forms enzmyes cut the damaged region hole in the DNA backbone is repaired by DNA polymerase and sealed by ligase
Mismatch Repair
Mismatch detected in newly synthesised DNA
new DNA strand cut and the mismatch and its neighbours are removed
hole in the DNA backbone is repaired by DNA polymerase and sealed by ligase
The DNA double strand break is farm more damaging what are two repair mechanisms.
Non-homologous end joining (causes mutations)
break is recognised and ring proteins attach to protect ends
the ends are removed
broken ends are ligated together
there is also Homology directed repair
broken DNA cut to find single strands
the DNA finds its sister chromatid
uses the sister as a template to copy, a perfect copy is produced
What is the multi step cancer model
lots of mutations build up of time until tumour becomes malignant
therefore replication stress stimulates carcniogenesis
mutations in the DNA damage repair systems can increase chances of cancer, as no repair of mutations
Explain tumours and their treatment in detail.
tumours are actually made of many sub clones (intra tumour heterogeneity)
different sub clones have different mutations and may be resistant to different treatments
heterogeneity promotes tumour evolution - DNA repair breaks and new sub clones develop
when treating colonal expansion is a problem , which can cause 2 issues
differential sensitivity and chemo induced mutagenisis
what are differential sensitivity and chemotherapy induced mutagenisis
Diff sens - where you treat a cancer, the main subclone is killed and it shrinks, a smaller sub clone is resistant and not killed, grows and tumour grows again
Chemo ind mut - when the drugs we treat with can actually cause mutations in the cancer creating new resistant sub clones
