Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair.
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Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, O'Connor KW, Konstantinopoulos PA, Elledge SJ, Boulton SJ, Yusufzai T, D'Andrea AD
Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair.
Nature. 2015 Feb 12;518(7538):258-62. doi: 10.1038/nature14184. Epub 2015 Feb 2.
- PubMed ID
- 25642963 [ View in PubMed]
- 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 theta (Poltheta 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 Poltheta interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Poltheta expression in EOCs. Knockdown of Poltheta in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Poltheta 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, Poltheta contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Poltheta-mediated repair in EOCs, and identify Poltheta as a novel druggable target for cancer therapy.