PARP1 is activated at telomeres upon G4 stabilization: Possible target for telomere-based therapy

E. Salvati, M. Scarsella, M. Porru, A. Rizzo, S. Iachettini, L. Tentori, G. Graziani, M. D'Incalci, M. F G Stevens, A. Orlandi, D. Passeri, E. Gilson, G. Zupi, C. Leonetti, A. Biroccio

Research output: Contribution to journalArticlepeer-review

Abstract

New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.

Original languageEnglish
Pages (from-to)6280-6293
Number of pages14
JournalOncogene
Volume29
Issue number47
DOIs
Publication statusPublished - Nov 25 2010

Keywords

  • combination therapy
  • G4 ligand
  • PARP1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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