Academic Journal
Targeting BRCA1 and BRCA2 deficiencies with G-Quadruplex-interacting compounds
| العنوان: | Targeting BRCA1 and BRCA2 deficiencies with G-Quadruplex-interacting compounds |
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| المؤلفون: | Zimmer, Jutta, Tacconi, Eliana M C, Folio, Cecilia, Badie, Sophie, Porru, Manuela, Klare, Kerstin, Tumiati, Manuela, Markkanen, Enni, Halder, Swagata, Ryan, Anderson, Jackson, Stephen P, Ramadan, Kristijan, Kuznetsov, Sergey G, Biroccio, Annamaria, Sale, Julian E, Tarsounas, Madalena |
| المصدر: | Zimmer, Jutta; Tacconi, Eliana M C; Folio, Cecilia; Badie, Sophie; Porru, Manuela; Klare, Kerstin; Tumiati, Manuela; Markkanen, Enni; Halder, Swagata; Ryan, Anderson; Jackson, Stephen P; Ramadan, Kristijan; Kuznetsov, Sergey G; Biroccio, Annamaria; Sale, Julian E; Tarsounas, Madalena (2016). Targeting BRCA1 and BRCA2 deficiencies with G-Quadruplex-interacting compounds. Molecular Cell, 61(3):449-460. |
| بيانات النشر: | Cell Press (Elsevier) |
| سنة النشر: | 2016 |
| المجموعة: | University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
| مصطلحات موضوعية: | Institute of Veterinary Pharmacology and Toxicology, 570 Life sciences, biology |
| الوصف: | G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1097-2765 |
| Relation: | https://www.zora.uzh.ch/id/eprint/120008/1/1-s2.0-S1097276515009387-main.pdf; info:pmid/26748828; urn:issn:1097-2765 |
| DOI: | 10.1016/j.molcel.2015.12.004 |
| الاتاحة: | https://www.zora.uzh.ch/id/eprint/120008/ https://doi.org/10.1016/j.molcel.2015.12.004 |
| Rights: | info:eu-repo/semantics/openAccess ; Creative Commons: Attribution 4.0 International (CC BY 4.0) ; http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.8EC26F46 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 10972765 |
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| DOI: | 10.1016/j.molcel.2015.12.004 |