DNA damage response & homologous recombination
The DNA damage response is the cell's set of repair crews. Single-strand breaks are patched by PARP; double-strand breaks by BRCA-dependent homologous recombination. Lose one crew and the cell survives; lose both and it dies. That is how PARP inhibitors work.
Single-strand breaks recruit PARP1 for base-excision repair. Unrepaired breaks collapse replication forks into double-strand breaks, repaired by homologous recombination (BRCA1, BRCA2, PALB2, RAD51) in S/G2 or by error-prone NHEJ/POLQ-mediated end joining. ATR senses replication stress and signals via CHK1; ATM senses double-strand breaks. HR-deficient tumours (BRCA mutation, HRD) depend on PARP, POLQ, and ATR: the basis of synthetic lethality. Resistance: BRCA reversion, 53BP1/Shieldin loss restoring HR, drug efflux.
In one picture
Two repair crews for a road: PARP fixes potholes, BRCA rebuilds collapsed bridges. A town that has lost its bridge crew (BRCA mutation) survives as long as potholes are fixed before they become bridge collapses. Block the pothole crew (PARP inhibitor) and the bridges fall.
Diagram
top- PARP inhibitors in BRCA/HRD ovarian, breast, prostate, pancreatic cancer
- Platinum chemotherapy (crosslinks) in HRD tumours
- ATR inhibitors (ceralasertib) in ATM-deficient or PARP-resistant tumours
- POLQ inhibitors (novobiocin analogues) in HRD
- PARP1-selective saruparib to widen therapeutic window
Pages like this
not linked directly; found by shared links- PersonAlan Ashworth
Shares Synthetic lethality approaches, PARP inhibitors, Olaparib, PARP.
- ProductRucaparib
Shares Base excision repair, PARP & alkylation damage, Double-strand break repair: HR versus end joining, PARP inhibitors, PARP.
- TermHomologous recombination deficiency (HRD)
Shares HRD & BRCA testing, Enabling characteristic: genome instability and mutation, Mutagenesis & mutational signatures, Base excision repair, PARP & alkylation damage.
- PersonAndrew Tutt
Shares Platinum agents, PARP inhibitors, Carboplatin, Olaparib.
- IdeaA functional test for homologous recombination deficiency validated across laboratories
Shares HRD & BRCA testing, PARP inhibitors, Olaparib, PARP.
- Key paperPAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours
Shares HRD & BRCA testing, Synthetic lethality approaches, PARP inhibitors, Olaparib.
- PathwayThe p53 network (guardian of the genome)
Shares WEE1, ATR, DNA replication stress, Synthetic lethality: paired dependencies.
- ProductIniparib
Shares Talazoparib, PARP inhibitors, Olaparib, PARP.