Targeting DNA repair inhibitors and Systemic cell lethality

Question 1

how often are DNA repair pathways activated?

Answer 1

always

Question 2

what determines which repair pathway is used?

Answer 2

the type of damage

Question 3

ss DNA damage uses which pathway

Answer 3

base excision repair pathway: BER

Question 4

what enzyme is used in the excision repair pathway?

Answer 4

PARP enzyme

Question 5

what pathway repairs DS breaks?

Answer 5

mismatch repair

Question 6

what does DS breaks lead to if not repaired?

Answer 6

cell lethality

Question 7

2 types of DNA repair when there’s a double stranded break?

Answer 7

homologous recombination pathway

non homologous joining

Question 8

which out of homologous recombination pathway and the

non homologous joining pathway is error prone? why?

Answer 8

non homologous enjoining is error prone as it sticks any ends together and doesn’t check sequence is correct

Question 9

why is the homologous recombination pathway error free

Answer 9

as it uses a template to repair

Question 10

3 ways to target DNA repair pathways as an anti cancer agent

Answer 10

PARP inhibitors
ATM inhibitors (homologous repair)
DNA PKs inhibitors (non homologous enjoining)

Question 11

what enzyme does non homologous enjoining use?

Answer 11

DNA PKs

Question 12

what enzyme does HR use?

Answer 12

BCRA

can also use ATM inhibitors

Question 13

why does inhibiting DNA repair help as an anti cancer agent

Answer 13

as many therapies cause DNA damage which kills the cell

preventing this repair will increase potential for cell death after the treatment

Question 14

what would you combine DNA repair inhibitors with? what will this result in?

Answer 14

with DNA damaging therapies

enhanced anti tumour response

Question 15

example of a DNA repair inhibitor and DNA damaging therapy combination?

Answer 15

PARP inhibitor + radiation

Question 16

by inhibiting PARP which pathway are you stopping? consequence

Answer 16

the BER pathway (base excision repair)

apoptosis

Question 17

base excision repair is _____ dependent. repairs ____ stand breaks

Answer 17

PARP

single

Question 18

do single strand breaks happen often?

Answer 18

yes commonly even in DNA replication

Question 19

if cells cannot use BER to med the single strand break what occurs?

Answer 19

a double strand break

Question 20

what happens when a single strand break turns into a ds break due to BER inactivity?

Answer 20

the ds break is then repaired by homologous recombination which is BRCA dependent

Question 21

what is HR dependent on?

Answer 21

BRCA

Question 22

why would PARP inhibitors on their own target cancer cells but not normal cells?

Answer 22

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

Question 23

why are cancer cells often defective in HR?

Answer 23

mutations in BRCA

Question 24

what is synthetic lethality

Answer 24

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)