An inverse correlation between homologous recombination and Polθ in epithelial ovarian cancers


Previous studies have shown DNA polymerase θ (Polθ) is involved in the error-prone microhomology-mediated end-joining (MMEJ) pathway, which is required for DNA repair. It is remain unknown whether Polθ is able to prevent genomic instability by regulating homologous recombination (HR) repair, which is often impaired in epithelial ovarian cancers (EOCs). Ceccaldi et al. reported that HR activity inversely correlated with Polθ expression in EOCs. The article was published in Nature.


In HR-proficient cells, knockdown of Polθ increases HR activity and RAD 51 nucleofilament assembly. On the other hand, in HR-deficient EOCs and mice with genetic inactivation of an HR gene, the inactivation of Polθ enhances embryonic lethality, indicating the anti-recombinase activity of Polθ keeps the genomic stability of HR-deficient cells. Mechanically, Polθ blocks RAD51-mediated recombination using its RAD51 binding motifs. The findings showed RAD51 is toxic to HR-deficient cells, in the absence of Polθ, suggesting Polθ as a novel therapeutic target for cancer treatment.


Nature. 2015 Feb 12;518(7538):258-62.

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