title: Homologous-recombination-deficient tumours are dependent on Polθ-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 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.
authors: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Raphael
authors: R
authors: Ceccaldi
authors: 1] Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA [3] Department of Molecular &Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Jessica C
authors: JC
authors: Liu
authors: Howard Hughes Medical Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Ravindra
authors: R
authors: Amunugama
authors: Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
authors: Ildiko
authors: I
authors: Hajdu
authors: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Benjamin
authors: B
authors: Primack
authors: DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall, South Mimms EN6 3LD, UK.
authors: Mark I R
authors: MI
authors: Petalcorin
authors: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Kevin W
authors: KW
authors: O'Connor
authors: Department of Medical Oncology, Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Panagiotis A
authors: PA
authors: Konstantinopoulos
authors: Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
authors: Stephen J
authors: SJ
authors: Elledge
authors: DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall, South Mimms EN6 3LD, UK.
authors: Simon J
authors: SJ
authors: Boulton
authors: 1] Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Timur
authors: T
authors: Yusufzai
authors: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Alan D
authors: AD
authors: D'Andrea
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000378:metabolism*; D020964:Embryo Loss; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency / Q000235:genetics; D005260:Female; D042822:Genomic Instability; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D059767:Recombinational DNA Repair / Q000235:genetics; D000097462:DNA Polymerase theta
chemical_list: D004259:DNA-Directed DNA Polymerase; D052236:Fanconi Anemia Complementation Group D2 Protein; D051135:Rad51 Recombinase; D000097462:DNA Polymerase theta; C499904:Fancd2 protein, mouse
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