Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds.

Zimmer J., Tacconi EMC., Folio C., Badie S., Porru M., Klare K., Tumiati M., Markkanen E., Halder S., Ryan A., Jackson SP., Ramadan K., Kuznetsov SG., Biroccio A., Sale JE., Tarsounas M.

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.

DOI

10.1016/j.molcel.2015.12.004

Type

Journal article

Journal

Mol Cell

Publication Date

04/02/2016

Volume

61

Pages

449 - 460

Keywords

Aminoquinolines, Animals, Antineoplastic Agents, BRCA1 Protein, BRCA2 Protein, Biomarkers, Tumor, Cell Proliferation, DNA Breaks, Double-Stranded, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, G-Quadruplexes, G2 Phase Cell Cycle Checkpoints, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Mad2 Proteins, Male, Mice, Nude, Molecular Targeted Therapy, Neoplasms, Picolinic Acids, Poly(ADP-ribose) Polymerase Inhibitors, RNA Interference, Telomere, Time Factors, Transfection, Tumor Burden, Tumor Suppressor p53-Binding Protein 1, Xenograft Model Antitumor Assays

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