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

Oncogene volume 29, pages 6280–6293 (2010)Cite this article

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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.

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References

  • Amé JC, Rolli V, Schreiber V, Niedergang C, Apiou F, Decker P et al. (1999). PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem 274: 17860–17868.

    Article  Google Scholar 

  • Amé JC, Spenlehauer C, de Murcia G . (2004). The PARP superfamily. Bioessays 26: 882–893.

    Article  Google Scholar 

  • Burkle A (eds). (2005). Poly(ADP-ribosyl)ation. Landes Biosciences: Austin, TX, USA.

    Google Scholar 

  • Brunori M, Mathieu N, Ricoul M, Bauwens S, Koering CE, Roborel de Climens A et al. (2006). TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts. Oncogene 25: 990–997.

    Article  CAS  Google Scholar 

  • Biroccio A, Amodei S, Benassi B, Scarsella M, Cianciulli A, Mottolese M et al. (2002). Reconstitution of hTERT restores tumorigenicity in melanoma-derived c-Myc low-expressing clones. Oncogene 21: 3011–3019.

    Article  CAS  Google Scholar 

  • Bakondi E, Bai P, Szabó EE, Hunyadi J, Gergely P, Szabó C et al. (2002). Detection of poly(ADP-ribose) polymerase activation in oxidatively stressed cells and tissues using biotinylated NAD substrate. J Histochem Cytochem 50: 91–98.

    Article  CAS  Google Scholar 

  • Cook BD, Dynek JN, Chang W, Shostak G, Smith S . (2002). Role for the related poly(ADP-ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol 22: 332–342.

    Article  CAS  Google Scholar 

  • Dantzer F, Giraud-Panis MJ, Jaco I, Amé JC, Schultz I, Blasco M et al. (2004). Functional interaction between poly(ADP-ribose) polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates TRF2. Mol Cell Biol 24: 1595–1607.

    Article  CAS  Google Scholar 

  • d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T et al. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature 426: 194–198.

    Article  CAS  Google Scholar 

  • de Lange T . (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19: 2100–2110.

    Article  CAS  Google Scholar 

  • Donigian JR, de Lange T . (2007). The role of the poly(ADP-ribose) polymerase tankyrase1 in telomere length control by the TRF1 component of the shelterin complex. J Biol Chem 282: 22662–22667.

    Article  CAS  Google Scholar 

  • Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB et al. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434: 917–921.

    Article  CAS  Google Scholar 

  • Gavathiotis E, Heald RA, Stevens MF, Searle MS . (2003). Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat. J Mol Biol 334: 25–36.

    Article  CAS  Google Scholar 

  • Gagné JP, Hendzel MJ, Droit A, Poirier GG . (2006). The expanding role of poly(ADP-ribose) metabolism: current challenges and new perspectives. Curr Opin Cell Biol 18: 145–151.

    Article  Google Scholar 

  • Geran RI, Greenberg NH, Macdonald MM, Shumacher AM, Abbott BJ . (1972). Protocols for screening chemical agents and natural products against animal tumors and other biological systems, 3rd edn. Cancer Chemother Rep 3: 1–88.

    Google Scholar 

  • Gomez M, Wu J, Schreiber V, Dunlap J, Dantzer F, Wang Y et al. (2006). PARP1 is a TRF2-associated poly(ADP-ribose)polymerase and protects eroded telomeres. Mol Biol Cell 17: 1686–1696.

    Article  CAS  Google Scholar 

  • Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H et al. (1999). Mammalian telomeres end in a large duplex loop. Cell 97: 503–514.

    Article  CAS  Google Scholar 

  • Heald RA, Modi C, Cookson JC, Hutchinson I, Laughton CA, Gowan SM et al. (2002). Antitumor polycyclic acridines 8 synthesis and telomerase-inhibitory activity of methylated pentacyclic acridinium salts. J Med Chem 45: 590–597.

    Article  CAS  Google Scholar 

  • Kaminker PG, Kim SH, Taylor RD, Zebarjadian Y, Funk WD, Morin GB et al. (2001). TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression. J Biol Chem 276: 35891–35899.

    Article  CAS  Google Scholar 

  • Kelland L . (2007). Targeting the limitless replicative potential of cancer: the telomerase/telomere pathway. Clin Cancer Res 13: 4960–4963.

    Article  CAS  Google Scholar 

  • Lenain C, Bauwens S, Amiard S, Brunori M, Giraud-Panis MJ, Gilson E . (2006). The Apollo 5′ exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr Biol 16: 1303–1310.

    Article  CAS  Google Scholar 

  • Leonetti C, Scarsella M, Riggio G, Rizzo A, Salvati E, D′Incalci M et al. (2008). G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors. Clin Cancer Res 14: 7284–7291.

    Article  CAS  Google Scholar 

  • Lord CJ, Ashworth A . (2008). Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol 8: 363–369.

    Article  CAS  Google Scholar 

  • Lindahl T, Satoh MS, Poirier GG, Klungland A . (1995). Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci 20: 405–411.

    Article  CAS  Google Scholar 

  • Makarov VL, Hirose Y, Langmore JP . (1997). Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell 88: 657–666.

    Article  CAS  Google Scholar 

  • Malanga M, Althaus FR . (2005). The role of poly(ADP-ribose) in the DNA damage signaling network. Biochem Cell Biol 83: 354–364.

    Article  CAS  Google Scholar 

  • Marcellini M, De Luca N, Riccioni T, Ciucci A, Orecchia A, Lacal PM et al. (2006). Increased melanoma growth and metastasis spreading in mice overexpressing placenta growth factor. Am J Pathol 169: 643–654.

    Article  CAS  Google Scholar 

  • Oganesian L, Bryan TM . (2007). Physiological relevance of telomeric G-quadruplex formation: a potential drug target. Bioessays 29: 155–165.

    Article  CAS  Google Scholar 

  • Orlandi A, Di Lascio A, Francesconi A, Scioli MG, Arcuri G, Ferlosio A et al. (2008). Stem cell marker expression and proliferation and apoptosis of vascular smooth muscle cells. Cell Cycle 7: 3889–3897.

    Article  CAS  Google Scholar 

  • Pleschke JM, Kleczkowska HE, Strohm M, Althaus FR . (2000). Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins. J Biol Chem 275: 40974–44080.

    Article  CAS  Google Scholar 

  • Plummer ER, Calvert H . (2007). Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res 13: 6252–6256.

    Article  CAS  Google Scholar 

  • Pisano C, De Cesare M, Beretta GL, Zuco V, Pratesi G, Penco S et al. (2008). Preclinical profile of antitumor activity of a novel hydrophilic campothecin, ST 1968. Mol Cancer Ther 7: 2051–2059.

    Article  CAS  Google Scholar 

  • Ratnam K, Low JA . (2007). Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. Clin Cancer Res 13: 1383–1388.

    Article  CAS  Google Scholar 

  • Rippmann JF, Damm K, Schnapp A . (2002). Functional characterization of the poly(ADP-ribose) polymerase activity of tankyrase 1, a potential regulator of telomere length. J Mol Biol 323: 217–224.

    Article  CAS  Google Scholar 

  • Rizzo A, Salvati E, Porru M, D′Angelo C, Stevens MF, D′Incalci M et al. (2009). Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway. Nucleic Acids Res 37: 5353–5364.

    Article  CAS  Google Scholar 

  • Schreiber V, Amé JC, Dollé P, Schultz I, Rinaldi B, Fraulob V et al. (2002). Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277: 23028–23036.

    Article  CAS  Google Scholar 

  • Salvati E, Leonetti C, Rizzo A, Scarsella M, Mottolese M, Galati R et al. (2007). Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect. J Clin Invest 117: 3236–3247.

    Article  CAS  Google Scholar 

  • Smith S, de Lange T . (1999). Cell cycle dependent localization of the telomeric PARP, tankyrase, to nuclear pore complexes and centrosomes. J Cell Sci 112 (Pt 21): 3649–3656.

    CAS  Google Scholar 

  • Sugimura K, Takebayashi S, Taguchi H, Takeda S, Okumura K . (2008). PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA. J Cell Biol 183: 1203–1212.

    Article  CAS  Google Scholar 

  • Takai H, Smogorzewska A, de Lange T . (2003). DNA damage foci at dysfunctional telomeres. Curr Biol 13: 1549–1556.

    Article  CAS  Google Scholar 

  • Tentori L, Graziani G . (2005). Chemopotentiation by PARP inhibitors in cancer therapy. Pharmacol Res 52: 25–33.

    Article  CAS  Google Scholar 

  • Tentori L, Leonetti C, Scarsella M, Muzi A, Mazzon E, Vergati M et al. (2006). Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma. FASEB J 20: 1709–1711.

    Article  CAS  Google Scholar 

  • Wright WE, Tesmer VM, Huffman KE, Levene SD, Shay JW . (1997). Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev 11: 2801–2809.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the Italian Association for Cancer Research (AIRC), Ministero della Salute and Ligue Nationale contre le Cancer (EG ‘équipe labellisée’). ES and MP are recipients of fellowships from the Italian Foundation for Cancer Research (FIRC). We thank Mrs Carmen D’Angelo for generating HT29 cells that express the luciferase gene and Mrs Adele Petricca for her helpful assistance in typing the manuscript. We are also grateful to Tania Merlino for the English revision.

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  1. Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, France

Authors and Affiliations

  1. Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy

    E Salvati, M Scarsella, M Porru, A Rizzo, S Iachettini, G Zupi, C Leonetti & A Biroccio

  2. Department of Neuroscience, University of Rome ‘Tor Vergata’, Rome, Italy

    L Tentori & G Graziani

  3. Department of Oncology, Pharmacological Research Institute ‘Mario Negri’, Milan, Italy

    M D'Incalci

  4. Center for Biomolecular Sciences, School of Pharmacy, the University of Nottingham, Nottingham, UK

    M F G Stevens

  5. Department of Biopathology and Image Diagnostics, Anatomic Pathology Institute, University of Rome ‘Tor Vergata’, Rome, Italy

    A Orlandi & D Passeri

  6. Laboratory of Biology and Pathology of Genomes CNRS, INSERM, University of Nice Sophia-Antipolis, Faculty of Medicine, France

    E Gilson

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Correspondence to A Biroccio.

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Salvati, E., Scarsella, M., Porru, M. et al. PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy. Oncogene 29, 6280–6293 (2010). https://doi.org/10.1038/onc.2010.344

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