Homologous-recombination-deficient tumours are dependent on Pol?-mediated repair.

ABSTRACT: Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair. Loss of HR accounts for the genomic instability of EOCs and for their cellular hyper-dependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms. Previous studies have implicated the DNA polymerase ? (Pol? also known as POLQ, encoded by POLQ) in a pathway required for the repair of DNA double-strand breaks, referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway. Whether Pol? interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Pol? expression in EOCs. Knockdown of Pol? in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Pol? in HR-deficient EOCs enhances cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, Pol? contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Pol?-mediated repair in EOCs, and identify Pol? as a novel druggable target for cancer therapy.

SUBMITTER: Ceccaldi R 

PROVIDER: S-EPMC4415602 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature