GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE312nnn/GSE312872/suppl/GSE312872_genome.csv.gzftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE312nnn/GSE312872/primary200OKOtherHomo sapiensOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312872GEOGSEfalseTargeting DKC1-mediated pseudouridylation combined with PARPi induces synthetic lethality in HR-proficient tumorsPoly(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.2026/08/14GSE312872GSM9356289GSM9356288GSM9356287GSM9356286GSM9356285GSM9356284GSM9356283GSM9356282GSM9356281GSM9356280GSM9356290GSM935627924676312872Homo sapiens