Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair

In studies in mammalian cells, polymerase theta (Polθ, also known as POLQ) is identified as the polymerase responsible for non-homologous end joining DNA repair; this DNA repair pathway acts in many tumours when homologous recombination is inactivated and the identification of the polymerase responsible may aid the development of new therapeutic approaches. The error-prone non-homologous end joining (NHEJ) DNA repair pathway is used as an alternative when the error-free homologous recombination pathway is compromised, or is the pathway of choice in some cellular contexts, such as in the immune system. After broken ends are paired via microhomology, NHEJ depends on DNA synthesis, but the identity of the polymerase involved was unclear. Two studies, from the laboratories of Agnel Sfeir and Alan D'Andrea, now implicate the mammalian POLQ gene, encoding the error-prone polymerase Polθ, in this process. Sfeir and colleagues show that upon telomere deprotection, Polθ is needed to prevent alternative end joining at telomeres, and chromosomal translations at non-telomeric sequences. D'Andrea and colleagues focus on the role of Polθ in cancer cells, and show that in a homologous-recombination-deficient background, the absence of Polθ results in a synthetic lethality, suggesting a possible therapeutic approach. Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair1. 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 mechanisms2,3,4,5. Previous studies have implicated the DNA polymerase θ (Polθ also known as POLQ, encoded by POLQ)6 in a pathway required for the repair of DNA double-strand breaks7,8,9, referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway10,11,12,13. Whether Polθ interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Polθ expression in EOCs. Knockdown of Polθ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Polθ 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, Polθ contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Polθ-mediated repair in EOCs, and identify Polθ as a novel druggable target for cancer therapy.