DNA damage response! Flashcards
What causes damage repaired by BER?
- ROS (far more ROS in tumours), natural ionising radiation, trapped topoisomerase 1, SAM, base deamination, cigarettes
- Drugs: TOPO1 poisons, antimetabolites, radiation (predictably), TMZ. Of course radiation hence why PARP so good with radiation!
Lesions and cause in HRR?
Unrepaired single stranded; manifests as stalled replication forks. Can be caused therapeutically by TMZ, topoI poisons, antimetabolites.
Lesion and cause in NHEJ?
ROS, radiation, trapped topo2 this time! Therapeutically by TMZ, ionising radiation, and topo1 poisons.
Cause of errors for DNA MMR?
Replication errors; slippage over repeats particularly. Also SAM and base deamination, as with BER. Therapeutically by TMZ and nucleoside analogues
Another therapy that targets BER?
APE-1 inhibitors i.e. methoxyamine. Apyrimidinic endonuclease 1. Key protein for BER. Inhibitors (methoxyamine) work by binding to the APE-1 substrate in DNA, thus potentiating TMZ and pemtrexed
PARP upregulation?
Seen in HCC and TNBC. Helps with chemotherapy resistance.
Normal PARP function?
- Activated by SSB; automodifies. Then accepts ADP-ribose from NAD+; uses ADP-ribose to form poly-ADP-ribose chain. This attracts the BER complex (DNA ligase and DNA polymerase)
How do PARP inhibitors work?
Inhibit PARP activity so no PAR chains formed and therefore BER complex cannot function, but also trap PARP to varying degrees, leading to stalled replication forks and thus double stranded breaks which are the main substrate for HRR.
BRCA-ness?
Patients likely to respond to PARP inhibitors even if have no mutations in BRCA. May be due to epigenetic silencing of BRCA. Can be mutations in ATM/CHEK2 (involved in HRR), high LOH, high proliferation rate (ki67 metrics), high p53 mutation rates, reduced BRCA mRNA, increased ID4!
What % of patients with HGSOC have HRR deficiency?
50% (germline or somatic BRCA mutations)
