Publication Date:
2015-02-03
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415602/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415602/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ceccaldi, Raphael -- Liu, Jessica C -- Amunugama, Ravindra -- Hajdu, Ildiko -- Primack, Benjamin -- Petalcorin, Mark I R -- O'Connor, Kevin W -- Konstantinopoulos, Panagiotis A -- Elledge, Stephen J -- Boulton, Simon J -- Yusufzai, Timur -- D'Andrea, Alan D -- 104558/Wellcome Trust/United Kingdom -- P50 CA168504/CA/NCI NIH HHS/ -- P50CA168504/CA/NCI NIH HHS/ -- R01 HL052725/HL/NHLBI NIH HHS/ -- R01HL52725/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 12;518(7538):258-62. doi: 10.1038/nature14184. Epub 2015 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. ; 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. ; Howard Hughes Medical Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall, South Mimms EN6 3LD, UK. ; Department of Medical Oncology, Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25642963" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Motifs
;
Animals
;
Cell Cycle
;
Cell Death
;
Cell Line, Tumor
;
*DNA Breaks, Double-Stranded
;
*DNA End-Joining Repair/genetics
;
DNA Replication
;
DNA-Directed DNA Polymerase/deficiency/*metabolism
;
Embryo Loss
;
Fanconi Anemia Complementation Group D2 Protein/deficiency/genetics
;
Female
;
Genomic Instability
;
*Homologous Recombination/genetics
;
Humans
;
Mice
;
Molecular Targeted Therapy
;
Neoplasms, Glandular and Epithelial/*genetics/*metabolism/pathology
;
Ovarian Neoplasms/*genetics/*metabolism/pathology
;
Protein Binding
;
Rad51 Recombinase/antagonists & inhibitors/metabolism
;
Recombinational DNA Repair/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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