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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)449-460
Number of pages12
JournalMolecular Cell
Volume61
Issue number3
DOIs
Publication statusPublished - Feb 4 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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