{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE313nnn/GSE313124/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE313124"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Targeting DKC1-mediated pseudouridylation combined with PARPi induces synthetic lethality in homologous recombination-proficient tumors [RNA-Seq]","description":"Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment landscape of BRCA-mutant tumors by exploiting synthetic lethality arising from homologous recombination (HR) deficiency. Yet, a substantial proportion of solid tumors remain HR-proficient and thus less responsive to PARPi, underscoring the need to develop strategies that extend their therapeutic scope. Here, we uncover a previously unrecognized synthetic lethal interaction between PARPi and dyskerin (DKC1), an RNA pseudouridine synthase. By analyzing a publicly available genome-wide CRISPR-Cas9 screen conducted in the presence of niraparib, we identified DKC1 as a top candidate whose loss synergized with PARP inhibition to selectively kill HR-proficient cancer cells. Mechanistically, DKC1 depletion impaired pseudouridylation of chromatin-associated RNAs, particularly promoter-associated RNAs, resulting in reduced chromatin accessibility and compromised recruitment of DNA repair factors, including BRCA1 and RAD21. This chromatin remodeling phenocopies HR deficiency, rendering HR-proficient cells vulnerable to PARPi. Notably, co-targeting DKC1 and PARP elicited potent antitumor effects in vitro and in multiple HR-proficient xenograft models. These findings identify DKC1-mediated pseudouridylation as a critical determinant of chromatin structure and DNA repair fidelity, and extend the conceptual framework of synthetic lethality from genetic HR defects to epigenetic regulation, offering a promising strategy to broaden the clinical utility of PARPi.","dates":{"publication":"2026/08/14"},"accession":"GSE313124","cross_references":{"GSM":["GSM9362365","GSM9362368","GSM9362367","GSM9362366"],"GPL":["24676"],"GSE":["313124"],"taxon":["Homo sapiens"]}}