{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE314nnn/GSE314448/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314448"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Low physiological pH drives P300-mediated acetylation of PARP1 and promotes PARP inhibitor resistance [Cut & Run]","description":"Resistance to PARP inhibitors (PARPi) remains a major clinical obstacle in epithelial ovarian carcinoma (EOC), ultimately limiting therapeutic efficacy and contributing to patient mortality. Here, we demonstrate that the acidic tumor microenvironment drives a novel mechanism of PARPi resistance. Decreasing the pH is sufficient to reduce PARPi anti-tumor efficacy in multiple in vitro and in vivo EOC models. Through three independent, epigenetically focused CRISPR/Cas9 screens conducted under low pH conditions, we identified p300 as a druggable target for overcoming pH-induced PARPi resistance. Mechanistically, in an unbiased functional proteomic evaluation we uncovered an ERK1/2–p300–PARP1 signaling axis activated under low pH, which alleviates PARPi-induced PARP1 trapping by promoting PARP1 K505 acetylation and thereby reducing replication fork collapse and associated DNA damage and driving PARPi resistance. Notably, in multiple in vivo patient-derived and syngeneic EOC models, two novel p300 bromodomain inhibitors, IACS-16559 and TT125-802, restore sensitivity to PARPi. Together, our findings establish p300 as a promising therapeutic target for overcoming pH-driven PARPi resistance in EOC.","dates":{"publication":"2026/07/13"},"accession":"GSE314448","cross_references":{"GSM":["GSM9396557","GSM9396560","GSM9396559","GSM9396558"],"GPL":["30882"],"GSE":["314448"],"taxon":["Homo sapiens"]}}