{"entity":{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","aka":[],"tldr":"A break through both strands of DNA is the most dangerous lesion a cell faces. Two crews compete to fix it: homologous recombination copies the answer from the sister chromosome (accurate, needs BRCA), while end joining simply glues the ends (fast, sloppy). Which crew wins decides whether PARP inhibitors and radiation kill the cell.","summary":"The MRN complex (MRE11-RAD50-NBS1) senses the break and activates ATM, which phosphorylates H2AX, CHK2 and p53. Pathway choice is set by resection: 53BP1-RIF1-Shieldin protect ends and favour classical NHEJ (Ku70/80, DNA-PKcs, Artemis, XRCC4-LIG4), dominant in G1 and used by radiation-damaged cells; BRCA1-CtIP promote resection in S/G2, RPA coats the single strand, and PALB2-BRCA2 load RAD51 to form a filament that invades the sister chromatid for accurate copying. Polymerase-theta-mediated end joining (TMEJ) is the backup that leaves microhomology-flanked deletions, the scar of HR deficiency. BRCA1/2, PALB2, RAD51C/D and ATM loss define HRD; such tumours cannot repair replication-associated breaks caused by PARP trapping, platinum crosslinks or topoisomerase poisons, and depend on POLQ and ATR. Reversion mutations, 53BP1/Shieldin loss (restoring resection in BRCA1-null cells), and fork protection restore HR under PARP-inhibitor pressure. DNA-PK inhibitors radiosensitise; ATM loss sensitises to ATR inhibition.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Homologous_recombination","links":[{"label":"Chang, Pannunzio, Adachi & Lieber, Non-homologous DNA end joining and alternative pathways to double-strand break repair (Nat Rev Mol Cell Biol 2017)","url":"https://doi.org/10.1038/nrm.2017.48"},{"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":["ovarian","tnbc","prostate","pancreatic","gallbladder"],"sections":[],"technologies":["parp-inhibitor","hrd-testing","platinum","imrt-igrt","sbrt","germline-testing","synthetic-lethality-approaches"],"targets":["brca","parp","atr","wee1"],"drugs":["olaparib","niraparib","rucaparib","talazoparib","carboplatin","cisplatin"],"companies":[],"institutions":[],"pathways":["ddr","replication-stress","base-excision-repair-parp","synthetic-lethality-map","cgas-sting"],"terms":["hrd","synthetic-lethality","mutational-signature","germline-vs-somatic","hereditary-cancer-syndromes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-lord-science","paper-chang-nat-rev-mol-cell-biol"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A torn page. The careful archivist (HR) fetches the twin copy from the shelf and transcribes it letter for letter; the hurried clerk (NHEJ) tapes the two halves together, losing a few words. Tumours missing the archivist survive on the clerk, so anything that adds more torn pages (PARP inhibitors, platinum, radiation) buries them.","nodes":[{"id":"dsb","label":"Double-strand break","x":45,"y":8},{"id":"mrn","label":"MRN → ATM → CHK2","x":45,"y":28,"targetId":"atr"},{"id":"53bp1","label":"53BP1-Shieldin (protect)","x":78,"y":28},{"id":"nhej","label":"NHEJ: Ku, DNA-PKcs, LIG4","x":78,"y":55},{"id":"res","label":"Resection: BRCA1-CtIP","x":15,"y":40,"targetId":"brca"},{"id":"rad51","label":"PALB2-BRCA2 → RAD51","x":15,"y":65,"targetId":"brca"},{"id":"hr","label":"Accurate HR (sister copy)","x":15,"y":90},{"id":"polq","label":"POLQ end joining (backup)","x":45,"y":90},{"id":"join","label":"Error-prone joining","x":78,"y":82},{"id":"parp","label":"PARP trapping → breaks","x":12,"y":8,"targetId":"parp"}],"edges":[{"from":"parp","to":"dsb","type":"activates"},{"from":"dsb","to":"mrn","type":"activates"},{"from":"mrn","to":"res","type":"activates"},{"from":"53bp1","to":"res","type":"inhibits"},{"from":"dsb","to":"nhej","type":"activates"},{"from":"53bp1","to":"nhej","type":"activates"},{"from":"res","to":"rad51","type":"activates"},{"from":"rad51","to":"hr","type":"activates"},{"from":"res","to":"polq","type":"activates"},{"from":"nhej","to":"join","type":"activates"},{"from":"polq","to":"join","type":"activates"}],"interventions":["PARP inhibitors (olaparib, niraparib, rucaparib, talazoparib) in BRCA/HRD ovarian, breast, prostate, pancreatic cancer","Platinum chemotherapy and radiation add breaks HR-deficient cells cannot fix","POLQ inhibitors (novobiocin analogues), ATR inhibitors after ATM loss, DNA-PK inhibitors with radiotherapy (trials)","HRD testing (genomic scars, BRCA sequencing) and RAD51 foci assays select patients; reversion mutations detected in ctDNA flag resistance"]},"route":"/pathways/homologous-recombination-repair/","neighbours":{"cancer":[{"id":"brca-palb2-pdac","kind":"cancer","name":"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma","route":"/cancers/brca-palb2-pdac/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"male-breast-cancer","kind":"cancer","name":"Male breast cancer","route":"/cancers/male-breast-cancer/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"pancreatic-acinar-cell-carcinoma","kind":"cancer","name":"Pancreatic acinar cell carcinoma","route":"/cancers/pancreatic-acinar-cell-carcinoma/"},{"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/"},{"id":"uterine-sarcoma","kind":"cancer","name":"Uterine sarcoma","route":"/cancers/uterine-sarcoma/"}],"technology":[{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"hrd-testing","kind":"technology","name":"HRD & BRCA testing","route":"/technologies/hrd-testing/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"},{"id":"platinum","kind":"technology","name":"Platinum agents","route":"/technologies/platinum/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"chek2","kind":"target","name":"CHEK2","route":"/targets/chek2/"},{"id":"lig4","kind":"target","name":"LIG4","route":"/targets/lig4/"},{"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":"rad51","kind":"target","name":"RAD51","route":"/targets/rad51/"},{"id":"wee1","kind":"target","name":"WEE1","route":"/targets/wee1/"}],"drug":[{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"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/"}],"pathway":[{"id":"base-excision-repair-parp","kind":"pathway","name":"Base excision repair, PARP & alkylation damage","route":"/pathways/base-excision-repair-parp/"},{"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":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/"}],"term":[{"id":"genome-wide-loss-of-heterozygosity","kind":"term","name":"Genome-wide loss of heterozygosity (gLOH)","route":"/terms/genome-wide-loss-of-heterozygosity/"},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic 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