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.
Journal article
Mol Cell
04/02/2016
61
449 - 460
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