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Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against <i>BRCA1/2</i>-mutated cancers through synthetic lethality. Unfortunately, most cases ultimately develop acquired resistance. Therefore, enhancing PARP inhibitor sensitivity and preventing resistance in those cells are an unmet clinical need. Here, we investigated the ability of paraspeckle component 1 (<i>PSPC1</i>), as an additional synthetic lethal partner with <i>BRCA1/2</i>, to enhance olaparib sensitivity in preclinical models of <i>BRCA1/2</i>-mutated breast and ovarian cancers. In vitro, the combined olaparib and <i>PSPC1</i> small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in <i>BRCA1/2</i>-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model. Mechanistically, olaparib monotherapy increased the expressions of p-ATM and DNA-PKcs, suggesting the activation of a DNA repair pathway, whereas combining <i>PSPC1</i> siRNA with olaparib decreased the expressions of p-ATM and DNA-PKcs again. As such, the combination increased the formation of γH2AX foci, indicating stronger DNA double-strand breaks. Subsequently, these DNA-damaged cells escaped G2/M checkpoint activation, as indicated by the suppression of p-cdc25C (Ser216) and p-cdc2 (Tyr15) after combination treatment. Finally, these cells entered mitosis, which induced increased apoptosis. Thus, this proves that <i>PSPC1</i> inhibition enhances olaparib sensitivity by targeting DNA damage response in our preclinical model. The combination of olaparib and <i>PSPC1</i> inhibition merits further clinical investigation to enhance PARP inhibitor efficacy.