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Tens of thousands of times a day a single DNA letter is oxidised or chemically scarred. A small crew snips it out and PARP marks the nick so it gets sealed. PARP inhibitors do not just switch PARP off; they trap it on the DNA, turning a harmless nick into a lethal break when the cell copies its DNA.
Damaged bases (8-oxoguanine, uracil, alkylated bases from temozolomide or endogenous methylation) are removed by glycosylases (OGG1, UNG, MPG), APE1 cuts the backbone, PARP1 binds the single-strand break and PARylates itself and histones to recruit XRCC1, Pol β fills the gap and LIG3 seals it (short-patch) or FEN1/LIG1 (long-patch). PARP inhibitors compete with NAD+ and, crucially, trap PARP1 on DNA (talazoparib >> olaparib > veliparib in trapping potency), so replication forks collide with the complex and collapse into double-strand breaks that only HR can fix, the mechanistic basis of BRCA synthetic lethality; PARP1-selective saruparib spares PARP2 and bone marrow. O6-methylguanine, the lethal TMZ lesion, is reversed directly by MGMT; MGMT promoter methylation predicts TMZ benefit in glioblastoma, and MMR is needed for TMZ toxicity. PARP inhibition also traps PARP at oxidative lesions from radiation and generates cytosolic DNA that fires cGAS-STING.
Potholes on a busy road. Normally a small crew fills them overnight and PARP is the foreman who cones them off. A PARP inhibitor glues the foreman to the pothole; in the morning the traffic (replication) hits him and the road collapses, and only the bridge-building crew (BRCA) could rebuild it.
Germline and tumour testing for homologous recombination repair genes is now standard in metastatic prostate cancer, and olaparib is approved for BRCA-mutated disease after a hormonal agent.
The trial behind the second PARP inhibitor licensed in prostate cancer, and the evidence that a somatic BRCA alteration predicts response as well as an inherited one. Together with TOPARP-A it is why tumour as well as germline sequencing is recommended in metastatic disease.
It establishes that PARP inhibitor resistance in prostate cancer is a restored repair pathway rather than a bypass, which is why platinum and PARP inhibitors lose activity together, and it is the argument for sampling plasma rather than one lesion at progression.
Three pathway pages on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Shares PARP inhibitors: Synthetic lethality in the clinic, Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors, PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration and the tags mechanism, mechanics-atlas.
Shares MGMT promoter methylation, DNA damage response & homologous recombination, Double-strand break repair: HR versus end joining, Homologous recombination deficiency (HRD) and the tags mechanism, mechanics-atlas.
Shares MGMT promoter methylation, cGAS-STING innate sensing, Lomustine (CCNU), Temozolomide and the tags mechanism, mechanics-atlas.
Shares ATR, DNA replication stress, DNA damage response & homologous recombination, Cytotoxic chemotherapy and the tags mechanism, mechanics-atlas.
Shares ATR, DNA replication stress, Ovarian cancer and the tags mechanism, mechanics-atlas.
Shares Synthetic lethality, Olaparib, BRCA1 / BRCA2 (HRD) and the tags mechanism, mechanics-atlas.
Shares DNA replication stress, Ovarian cancer and the tags mechanism, mechanics-atlas.
Shares Ovarian cancer, Prostate cancer and the tags mechanism, mechanics-atlas.