{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:17:13Z","timestamp":1787825833895,"version":"build-2784847793"},"reference-count":29,"publisher":"Wiley","issue":"5-7","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":72,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Poly(ADP\u2010ribose) polymerase (PARP) inhibitors (PARPi) have transformed precision oncology by exploiting synthetic lethality in homologous recombination (HR)\u2010deficient cancers, with multiple FDA\u2010approved agents targeting\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    \u2010mutant tumors. Despite initial efficacy, resistance inevitably emerges, limiting long\u2010term clinical benefit. This review synthesizes emerging mechanistic insights into PARPi response and resistance. Recent evidence reframes PARP inhibition cytotoxicity through a transcription\u2013replication conflict model and identifies single\u2010stranded DNA gaps as the primary lethal lesion in HR\u2010deficient cells, rather than double\u2010strand breaks. These findings suggest that resistance reflects restoration of replication gap suppression or resolution of transcription\u2013replication stress. We further highlight DNA ligase III as a collateral vulnerability in\n                    <jats:italic>53BP1<\/jats:italic>\n                    \u2010deficient resistant tumors, and discuss proteolysis\u2010targeting chimera (PROTAC)\u2010based PARP1 degraders as a strategy to overcome resistance and induce alternative cell death pathways. Established resistance mechanisms\u2014including\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    reversion mutations, shieldin complex loss,\n                    <jats:italic>RAD51<\/jats:italic>\n                    hyperactivation, and pharmacokinetic alterations\u2014are reconsidered within this updated framework. Combination strategies with ATR inhibitors show promising clinical activity in PARPi\u2010resistant HR\u2010deficient ovarian cancer. Finally, we propose an integrated biomarker framework combining HRD scar assays, functional\n                    <jats:italic>RAD51<\/jats:italic>\n                    foci analysis, replication gap profiling, and circulating tumor DNA (ctDNA) monitoring to enable dynamic resistance tracking.\n                  <\/jats:p>","DOI":"10.1002\/em.70076","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T06:59:22Z","timestamp":1786604362000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms of\n                    <scp>PARP<\/scp>\n                    Inhibitor Resistance: From Replication Gap Biology and Transcription\u2013Replication Conflicts to\n                    <scp>PROTAC<\/scp>\n                    \u2010Based Next\u2010Generation Strategies"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0181-9336","authenticated-orcid":false,"family":"Abinawanto","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Mathematics and Natural Sciences Universitas Indonesia  Depok Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5206-2110","authenticated-orcid":false,"given":"Alfi","family":"Sophian","sequence":"additional","affiliation":[{"name":"The Indonesian Food and Drug Authority (BPOM)  Jakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03443"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201007277\u20102"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.06.010"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03445"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010018\u20100612\u20108"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010022\u201000535\u20105"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djy085"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/narcan\/zcac042"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08467"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60637"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010cancerbio\u2010042324\u2010103725"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201017127\u20102"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001893\u20102"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adt1210"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI181062"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omton.2025.200934"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00670"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam7344"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S272199"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611310"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12266"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201012\u20102753"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.09.005"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007217\u20102"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698\u2010024\u201000526\u20109"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201022\u20102444"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115328"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2025.103847"},{"key":"e_1_2_14_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010025\u201002355\u20101"}],"container-title":["Environmental 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