{"entity":{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/DNA_repair","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/DNA_repair"}],"tags":[],"related":[],"cancers":["ovarian","tnbc","prostate","pancreatic"],"sections":[],"technologies":["parp-inhibitor","hrd-testing","synthetic-lethality-approaches","platinum","parp-pet"],"targets":["parp","brca","atr","wee1","tp53"],"drugs":["olaparib","niraparib","talazoparib","carboplatin"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"analogy":"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.","nodes":[{"id":"ssb","label":"Single-strand break","x":20,"y":8},{"id":"parp","label":"PARP1","x":20,"y":28,"targetId":"parp"},{"id":"fork","label":"Replication fork collapse","x":50,"y":45},{"id":"atr","label":"ATR / CHK1","x":80,"y":30,"targetId":"atr"},{"id":"dsb","label":"Double-strand break","x":50,"y":62},{"id":"brca","label":"BRCA1/2-RAD51 (HR)","x":25,"y":82,"targetId":"brca"},{"id":"nhej","label":"NHEJ / POLQ (error-prone)","x":75,"y":82},{"id":"fix","label":"Accurate repair","x":25,"y":97},{"id":"death","label":"Genomic collapse / death","x":75,"y":97}],"edges":[{"from":"ssb","to":"parp","type":"activates"},{"from":"parp","to":"fork","type":"inhibits"},{"from":"ssb","to":"fork","type":"activates"},{"from":"fork","to":"dsb","type":"activates"},{"from":"atr","to":"fork","type":"inhibits"},{"from":"dsb","to":"brca","type":"activates"},{"from":"dsb","to":"nhej","type":"activates"},{"from":"brca","to":"fix","type":"activates"},{"from":"nhej","to":"death","type":"activates"}],"interventions":["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"]},"route":"/pathways/ddr/","neighbours":{"cancer":[{"id":"tnbc-basal-like-1","kind":"cancer","name":"Basal-like 1 triple-negative breast cancer (BL1)","route":"/cancers/tnbc-basal-like-1/"},{"id":"brca-palb2-pdac","kind":"cancer","name":"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma","route":"/cancers/brca-palb2-pdac/"},{"id":"brca-associated-tnbc","kind":"cancer","name":"BRCA-associated triple-negative breast cancer","route":"/cancers/brca-associated-tnbc/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"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":"hrd-testing","kind":"technology","name":"HRD & BRCA testing","route":"/technologies/hrd-testing/"},{"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":"platinum","kind":"technology","name":"Platinum agents","route":"/technologies/platinum/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"target":[{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"chek1","kind":"target","name":"CHEK1","route":"/targets/chek1/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"polk","kind":"target","name":"POLK","route":"/targets/polk/"},{"id":"polq","kind":"target","name":"POLQ","route":"/targets/polq/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"wee1","kind":"target","name":"WEE1","route":"/targets/wee1/"}],"drug":[{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}],"paper":[{"id":"paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","kind":"paper","name":"Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer","route":"/key-papers/paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018/"},{"id":"paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014","kind":"paper","name":"Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer","route":"/key-papers/paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014/"},{"id":"paper-bailey-molecular-subtypes-pancreatic-nature-2016","kind":"paper","name":"Genomic analyses identify molecular subtypes of pancreatic cancer","route":"/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/"},{"id":"paper-castro-germline-brca-prostate-outcomes-jco-2013","kind":"paper","name":"Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis and poor survival outcomes in prostate cancer","route":"/key-papers/paper-castro-germline-brca-prostate-outcomes-jco-2013/"},{"id":"paper-palles-germline-pole-pold1-proofreading-nat-genet-2013","kind":"paper","name":"Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas","route":"/key-papers/paper-palles-germline-pole-pold1-proofreading-nat-genet-2013/"},{"id":"paper-lehmann-tnbc-subtypes-jci-2011","kind":"paper","name":"Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies","route":"/key-papers/paper-lehmann-tnbc-subtypes-jci-2011/"},{"id":"paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","kind":"paper","name":"Inherited DNA-repair gene mutations in men with metastatic prostate cancer","route":"/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/"},{"id":"paper-isaacsson-velho-intraductal-germline-dna-repair-prostate-2018","kind":"paper","name":"Intraductal and ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer","route":"/key-papers/paper-isaacsson-velho-intraductal-germline-dna-repair-prostate-2018/"},{"id":"paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019","kind":"paper","name":"POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer","route":"/key-papers/paper-polo-olaparib-maintenance-gbrca-pancreatic-nejm-2019/"},{"id":"paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019","kind":"paper","name":"Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines","route":"/key-papers/paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019/"},{"id":"paper-waddell-whole-genomes-pancreatic-nature-2015","kind":"paper","name":"Whole genomes redefine the mutational landscape of pancreatic cancer","route":"/key-papers/paper-waddell-whole-genomes-pancreatic-nature-2015/"}],"roadmap":[{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/"},{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","route":"/roadmaps/tnbc-roadmap/"}],"biomarker":[{"id":"hrr-gene-mutation","kind":"biomarker","name":"Homologous recombination repair gene mutation in prostate cancer","route":"/biomarkers/hrr-gene-mutation/"}],"pairing":[{"id":"parp-plus-arpi","kind":"pairing","name":"PARP inhibitor + AR pathway inhibitor (prostate)","route":"/pairings/parp-plus-arpi/"},{"id":"platinum-plus-hrd","kind":"pairing","name":"Platinum chemotherapy in HRD tumours","route":"/pairings/platinum-plus-hrd/"}],"idea":[{"id":"idea-bio1-mutagenesis-blockade-rev1","kind":"idea","name":"Turn off the error-prone repair that manufactures resistance mutations","route":"/ideas/idea-bio1-mutagenesis-blockade-rev1/"},{"id":"idea-chip-risk-modifiers","kind":"idea","name":"Which patients' blood clones will become leukaemia after treatment?","route":"/ideas/idea-chip-risk-modifiers/"}],"pathway":[{"id":"base-excision-repair-parp","kind":"pathway","name":"Base excision repair, PARP & alkylation damage","route":"/pathways/base-excision-repair-parp/"},{"id":"breast-cancer-signalling","kind":"pathway","name":"Breast cancer (KEGG map)","route":"/pathways/breast-cancer-signalling/"},{"id":"dna-replication-licensing","kind":"pathway","name":"DNA replication & origin licensing","route":"/pathways/dna-replication-licensing/"},{"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/"},{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"},{"id":"pancreatic-cancer-signalling","kind":"pathway","name":"Pancreatic cancer (KEGG map)","route":"/pathways/pancreatic-cancer-signalling/"},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/"}],"term":[{"id":"genome-instability-mutation","kind":"term","name":"Enabling characteristic: genome instability and mutation","route":"/terms/genome-instability-mutation/"}],"company":[{"id":"artios-pharma","kind":"company","name":"Artios Pharma","route":"/companies/artios-pharma/"}]}}