Targeting DKC1-mediated pseudouridylation combined with PARPi induces synthetic lethality in homologous recombination-proficient tumors

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.