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Nucleic Acids Research 2005 33(13):4182-4190; doi:10.1093/nar/gki722
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Published online 28 July 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

Preferential binding of a G-quadruplex ligand to human chromosome ends

Christine Granotier1, Gaëlle Pennarun1,2, Lydia Riou1, Françoise Hoffschir1, Laurent R. Gauthier1, Anne De Cian2, Dennis Gomez4, Eliane Mandine3, Jean-François Riou4, Jean-Louis Mergny2, Patrick Mailliet3, Bernard Dutrillaux1 and François D. Boussin1,*

1LRP, DRR, CEA 92265 Fontenay-aux-Roses, France 2Laboratoire de Biophysique, INSERM U565, CNRS UMR 5153, Muséum National d'Histoire Naturelle USM 503 75005 Paris, France 3Aventis Pharma SA, Centre de Recherche de Paris 94403 Vitry-sur-Seine, France 4Laboratoire d'Onco-Pharmacologie, JE 2428, Université de Reims Champagne-Ardenne 51096, Reims, France

*To whom correspondance should be addressed. Tel: +33 1 46 54 97 91; Fax: +33 1 46 54 97 02; Email: boussin{at}cea.fr

Received April 19, 2005. Revised June 17, 2005. Accepted July 5, 2005.

The G-overhangs of telomeres are thought to adopt particular conformations, such as T-loops or G-quadruplexes. It has been suggested that G-quadruplex structures could be stabilized by specific ligands in a new approach to cancer treatment consisting in inhibition of telomerase, an enzyme involved in telomere maintenance and cell immortality. Although the formation of G-quadruplexes was demonstrated in vitro many years ago, it has not been definitively demonstrated in living human cells. We therefore investigated the chromosomal binding of a tritiated G-quadruplex ligand, 3H-360A (2,6-N,N'-methyl-quinolinio-3-yl)-pyridine dicarboxamide [methyl-3H]. We verified the in vitro selectivity of 3H-360A for G-quadruplex structures by equilibrium dialysis. We then showed by binding experiments with human genomic DNA that 3H-360A has a very potent selectivity toward G-quadruplex structures of the telomeric 3'-overhang. Finally, we performed autoradiography of metaphase spreads from cells cultured with 3H-360A. We found that 3H-360A was preferentially bound to chromosome terminal regions of both human normal (peripheral blood lymphocytes) and tumor cells (T98G and CEM1301). In conclusion, our results provide evidence that a specific G-quadruplex ligand interacts with the terminal ends of human chromosomes. They support the hypothesis that G-quadruplex ligands induce and/or stabilize G-quadruplex structures at telomeres of human cells.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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