Targeting DNA repair inhibitors and Systemic cell lethality Flashcards
how often are DNA repair pathways activated?
always
what determines which repair pathway is used?
the type of damage
ss DNA damage uses which pathway
base excision repair pathway: BER
what enzyme is used in the excision repair pathway?
PARP enzyme
what pathway repairs DS breaks?
mismatch repair
what does DS breaks lead to if not repaired?
cell lethality
2 types of DNA repair when there’s a double stranded break?
homologous recombination pathway
non homologous joining
which out of homologous recombination pathway and the
non homologous joining pathway is error prone? why?
non homologous enjoining is error prone as it sticks any ends together and doesn’t check sequence is correct
why is the homologous recombination pathway error free
as it uses a template to repair
3 ways to target DNA repair pathways as an anti cancer agent
PARP inhibitors
ATM inhibitors (homologous repair)
DNA PKs inhibitors (non homologous enjoining)
what enzyme does non homologous enjoining use?
DNA PKs
what enzyme does HR use?
BCRA
can also use ATM inhibitors
why does inhibiting DNA repair help as an anti cancer agent
as many therapies cause DNA damage which kills the cell
preventing this repair will increase potential for cell death after the treatment
what would you combine DNA repair inhibitors with? what will this result in?
with DNA damaging therapies
enhanced anti tumour response
example of a DNA repair inhibitor and DNA damaging therapy combination?
PARP inhibitor + radiation
by inhibiting PARP which pathway are you stopping? consequence
the BER pathway (base excision repair)
apoptosis
base excision repair is _____ dependent. repairs ____ stand breaks
PARP
single
do single strand breaks happen often?
yes commonly even in DNA replication
if cells cannot use BER to med the single strand break what occurs?
a double strand break
what happens when a single strand break turns into a ds break due to BER inactivity?
the ds break is then repaired by homologous recombination which is BRCA dependent
what is HR dependent on?
BRCA
why would PARP inhibitors on their own target cancer cells but not normal cells?
as cancer cells often have defects in the backup repair pathways.
HR is defected so cant repair ds breaks when PARP is inhibited in the BER pathway
= systemic lethality
why are cancer cells often defective in HR?
mutations in BRCA
what is synthetic lethality
a drug approach which is normally tolerated is made lethal because the cancer lacks a back up pathway (due to BRCA mutations which are common in cancer)
