Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway.
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.
Rizzo
Angela
A
Department of Experimental Chemotherapy, Regina Elena Cancer Institute, 00158 Rome, Italy.
Salvati
Erica
E
Porru
Manuela
M
D'Angelo
Carmen
C
Stevens
Malcolm F
MF
D'Incalci
Maurizio
M
Leonetti
Carlo
C
Gilson
Eric
E
Zupi
Gabriella
G
Biroccio
Annamaria
A
D000166:Acridines / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016615:Telomere / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases