{"entity":{"id":"base-excision-repair-parp","kind":"pathway","name":"Base excision repair, PARP & alkylation damage","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Base_excision_repair","links":[{"label":"Caldecott, Single-strand break repair and genetic disease (Nat Rev Genet 2008)","url":"https://doi.org/10.1038/nrg2380"},{"label":"Lord & Ashworth, PARP inhibitors: synthetic lethality in the clinic (Science 2017)","url":"https://doi.org/10.1126/science.aam7344"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["glioblastoma","ovarian","prostate","tnbc"],"sections":[],"technologies":["parp-inhibitor","parp-pet","radionuclide-parp-combination","cytotoxic-chemotherapy"],"targets":["parp","brca","atr"],"drugs":["olaparib","niraparib","rucaparib","talazoparib","temozolomide","lomustine"],"companies":[],"institutions":[],"pathways":["ddr","homologous-recombination-repair","cgas-sting","replication-stress"],"terms":["mgmt","synthetic-lethality","hrd","dna-alkylator-payloads"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-lord-science","paper-caldecott-nat-rev-genet"],"journals":[],"dependsOn":[],"notes":[],"analogy":"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.","nodes":[{"id":"les","label":"Oxidised / alkylated base","x":12,"y":15},{"id":"mgmt","label":"MGMT direct reversal","x":12,"y":45},{"id":"glyc","label":"Glycosylase → APE1","x":40,"y":15},{"id":"ssb","label":"Single-strand break","x":68,"y":15},{"id":"parp","label":"PARP1 → XRCC1","x":68,"y":45,"targetId":"parp"},{"id":"polb","label":"Pol β, LIG3 seal","x":92,"y":60},{"id":"trap","label":"PARP trapped on DNA","x":40,"y":72},{"id":"fork","label":"Fork collapse → DSB","x":68,"y":90},{"id":"hr","label":"HR (BRCA) rescue","x":92,"y":90,"targetId":"brca"},{"id":"tmz","label":"Temozolomide, radiation","x":12,"y":78}],"edges":[{"from":"les","to":"glyc","type":"activates"},{"from":"mgmt","to":"les","type":"inhibits"},{"from":"glyc","to":"ssb","type":"activates"},{"from":"ssb","to":"parp","type":"activates"},{"from":"parp","to":"polb","type":"activates"},{"from":"tmz","to":"les","type":"activates"},{"from":"parp","to":"trap","type":"activates"},{"from":"trap","to":"fork","type":"activates"},{"from":"hr","to":"fork","type":"inhibits"}],"interventions":["PARP inhibitors: talazoparib (strongest trapper), olaparib, niraparib, rucaparib; PARP1-selective saruparib","Temozolomide in MGMT-methylated glioblastoma; lomustine, dacarbazine as alkylators","PARP inhibitor + radiotherapy or + TMZ combinations, limited by marrow toxicity; PARP-radioligand combinations in trials","PARP PET imaging to quantify target"]},"route":"/pathways/base-excision-repair-parp/","neighbours":{"cancer":[{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"technology":[{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"},{"id":"parp-pet","kind":"technology","name":"PARP PET","route":"/technologies/parp-pet/"},{"id":"radionuclide-parp-combination","kind":"technology","name":"Radioligand plus DNA-repair inhibitor combinations","route":"/technologies/radionuclide-parp-combination/"}],"target":[{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"xrcc1","kind":"target","name":"XRCC1","route":"/targets/xrcc1/"}],"drug":[{"id":"lomustine","kind":"drug","name":"Lomustine (CCNU)","route":"/drugs/lomustine/"},{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"rucaparib","kind":"drug","name":"Rucaparib","route":"/drugs/rucaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"},{"id":"temozolomide","kind":"drug","name":"Temozolomide","route":"/drugs/temozolomide/"}],"pathway":[{"id":"cgas-sting","kind":"pathway","name":"cGAS-STING innate sensing","route":"/pathways/cgas-sting/"},{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"},{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"}],"term":[{"id":"dna-alkylator-payloads","kind":"term","name":"DNA alkylator payloads","route":"/terms/dna-alkylator-payloads/"},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"mgmt","kind":"term","name":"MGMT promoter methylation","route":"/terms/mgmt/"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"paper":[{"id":"paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017","kind":"paper","name":"Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors","route":"/key-papers/paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017/"},{"id":"paper-lord-science","kind":"paper","name":"PARP inhibitors: Synthetic lethality in the clinic","route":"/key-papers/paper-lord-science/"},{"id":"paper-profound-nejm-2020","kind":"paper","name":"PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations","route":"/key-papers/paper-profound-nejm-2020/"},{"id":"paper-caldecott-nat-rev-genet","kind":"paper","name":"Single-strand break repair and genetic disease","route":"/key-papers/paper-caldecott-nat-rev-genet/"},{"id":"paper-abida-triton2-rucaparib-brca-jco-2020","kind":"paper","name":"TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration","route":"/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/"}],"biomarker":[{"id":"hrr-gene-mutation","kind":"biomarker","name":"Homologous recombination repair gene mutation in prostate cancer","route":"/biomarkers/hrr-gene-mutation/"}]}}