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

Nature. 2015 Feb 12;518(7538):258-62. doi: 10.1038/nature14184. Epub 2015 Feb 2.

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 θ (Polθ 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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Carcinoma, Ovarian Epithelial
  • Cell Cycle
  • Cell Death
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair* / genetics
  • DNA Replication
  • DNA-Directed DNA Polymerase / deficiency
  • DNA-Directed DNA Polymerase / metabolism*
  • Embryo Loss
  • Fanconi Anemia Complementation Group D2 Protein / deficiency
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Female
  • Genomic Instability
  • Homologous Recombination* / genetics
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Neoplasms, Glandular and Epithelial / genetics*
  • Neoplasms, Glandular and Epithelial / metabolism*
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Protein Binding
  • Rad51 Recombinase / antagonists & inhibitors
  • Rad51 Recombinase / metabolism
  • Recombinational DNA Repair / genetics

Substances

  • Fancd2 protein, mouse
  • Fanconi Anemia Complementation Group D2 Protein
  • DNA polymerase theta
  • Rad51 Recombinase
  • DNA-Directed DNA Polymerase