The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair
Open accessAbstract
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.
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Citations
Cites
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Self-citationThe controlling role of ATM in homologous recombinational repair of DNA damage
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Self-citationHematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1
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Cited by
Mechanisms of DNA damage, repair, and mutagenesis
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“In addition, loss of FANCD2 confers a synthetic lethal phe- notype in POL u null mice [Nguyen et al., 2014; Ceccaldi et al., 2015; Howard et al., 2015].”
The multifaceted roles of PARP1 in DNA repair and chromatin remodelling
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Repair Pathway Choices and Consequences at the Double-Strand Break
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Self-citationDNA double-strand break repair-pathway choice in somatic mammalian cells
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State-of-the-art strategies for targeting the DNA damage response in cancer
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Metadata
- Authors
- Ceccaldi, R., Liu, J. C., Amunugama, R., Hajdu, I., Primack, B., Petalcorin, M. I. R., O’Connor, K. W., Konstantinopoulos, P. A., Elledge, S. J., Boulton, S. J., Yusufzai, T., & D’Andrea, A. D.
- Venue
- Nature
- Published
- 2015-02-02
- Volume
- 518
- Issue
- 7538
- Pages
- 258-262
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1982957001
- Cited by
- 903
- References
- 8
- FWCI
- 27.92
- Type
- journal article
- Language
- en
- Open access
- green
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- Ceccaldi, R., Liu, J. C., Amunugama, R., Hajdu, I., Primack, B., Petalcorin, M. I. R., O’Connor, K. W., Konstantinopoulos, P. A., Elledge, S. J., Boulton, S. J., Yusufzai, T., & D’Andrea, A. D. (2015). Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature. https://doi.org/10.1038/nature14184
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