Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds
| Autor: | Jutta, Zimmer, Eliana M C, Tacconi, Cecilia, Folio, Sophie, Badie, Manuela, Porru, Kerstin, Klare, Manuela, Tumiati, Enni, Markkanen, Swagata, Halder, Anderson, Ryan, Stephen P, Jackson, Kristijan, Ramadan, Sergey G, Kuznetsov, Annamaria, Biroccio, Julian E, Sale, Madalena, Tarsounas |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Time Factors Mice Nude Antineoplastic Agents Poly(ADP-ribose) Polymerase Inhibitors Transfection Article Neoplasms Biomarkers Tumor Animals Humans DNA Breaks Double-Stranded Molecular Targeted Therapy Picolinic Acids Cell Proliferation BRCA2 Protein Dose-Response Relationship Drug BRCA1 Protein Intracellular Signaling Peptides and Proteins Telomere Xenograft Model Antitumor Assays Tumor Burden G-Quadruplexes G2 Phase Cell Cycle Checkpoints HEK293 Cells Drug Resistance Neoplasm Mad2 Proteins Aminoquinolines RNA Interference Tumor Suppressor p53-Binding Protein 1 |
| Zdroj: | Molecular Cell |
| ISSN: | 1097-4164 |
| Popis: | Summary 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. Graphical Abstract Highlights • G4 formation on the G-rich strand drives telomere fragility in HR-deficient cells • G4-stabilizing compounds reduce viability of cells lacking BRCA1, BRCA2, or RAD51 • G4 toxicity stems from excessive replication stress and DNA damage accumulation • Olaparib-resistant, BRCA-defective cells are sensitive to G4-stabilizing compounds Zimmer et al. discovered that homologous recombination activities of BRCA1 and BRCA2 facilitate replication of genomic regions with G-quadruplex-forming potential, including telomeres, and suppress genomic instability stemming from inefficient replication of these sites. G4-stabilizing compounds are toxic to BRCA1- and BRCA2-deficient cells, highlighting their therapeutic potential in targeting BRCA deficiency. |
| Databáze: | OpenAIRE |
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