Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway

Angela Rizzo, Erica Salvati, Manuela Porru, Carmen D'Angelo, Malcolm F. Stevens, Maurizio D'Incalci, Carlo Leonetti, Eric Gilson, Gabriella Zupi, Annamaria Biroccio

Research output: Contribution to journalArticle

Abstract

Functional telomeres are required to maintain the replicative ability of cancer cells and represent putative targets for G-quadruplex (G4) ligands. Here, we show that the pentacyclic acridinium salt RHPS4, one of the most effective and selective G4 ligands, triggers damages in cells traversing S phase by interfering with telomere replication. Indeed, we found that RHPS4 markedly reduced BrdU incorporation at telomeres and altered the dynamic association of the telomeric proteins TRF1, TRF2 and POT1, leading to chromosome aberrations such as telomere fusions and telomere doublets. Analysis of the molecular damage pathway revealed that RHPS4 induced an ATR-dependent ATM signaling that plays a functional role in the cellular response to RHPS4 treatment. We propose that RHPS4, by stabilizing G4 DNA at telomeres, impairs fork progression and/or telomere processing resulting in telomere dysfunction and activation of a replication stress response pathway. The detailed understanding of the molecular mode of action of this class of compounds makes them attractive tools to understand telomere biology and provides the basis for a rational use of G4 ligands for the therapy of cancer.

Original languageEnglish
Article numbergkp582
Pages (from-to)5353-5364
Number of pages12
JournalNucleic Acids Research
Volume37
Issue number16
DOIs
Publication statusPublished - Jul 13 2009

ASJC Scopus subject areas

  • Genetics

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