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Nucleic Acids Research Advance Access originally published online on May 1, 2008
Nucleic Acids Research 2008 36(11):3531-3538; doi:10.1093/nar/gkn231
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Nucleic Acids Research, 2008, Vol. 36, No. 11 3531-3538
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Sequence-specific DNA cleavage mediated by bipyridine polyamide conjugates

Philippe Simon1,2,3, Fabio Cannata1,2,3, Loïc Perrouault1,2,3, Ludovic Halby1,2,3, Jean-Paul Concordet4,5, Alexandre Boutorine1,2,3, Vladimir Ryabinin6, Alexandre Sinyakov6 and Carine Giovannangeli1,2,3,*

1CNRS, UMR5153, 2Inserm, U565, 3Museum National d'Histoire Naturelle, USM503, Paris, F-75005, 4Institut Cochin, Université Paris Descartes, CNRS UMR8104, 5Inserm U567, 24 rue du Fbg St-Jacques, 75014 Paris, France and 6Institute of Molecular Biology, State Research Center of Virology and Biotechnology ‘Vector’, Koltsovo, Novosibirsk region 630559, Russia

*To whom the correspondence should be addressed. Tel: +33 1 40793711; Fax: +33 1 40793705; Email: giovanna{at}mnhn.fr

Received February 20, 2008. Revised April 10, 2008. Accepted April 11, 2008.

The design of molecules that damage a selected DNA sequence provides a formidable opportunity for basic and applied biology. For example, such molecules offer new prospects for controlled manipulation of the genome. The conjugation of DNA-code reading molecules such as polyamides to reagents that induce DNA damages provides an approach to reach this goal. In this work, we showed that a bipyridine conjugate of polyamides was able to induce sequence-specific DNA breaks in cells. We synthesized compounds based on two polyamide parts linked to bipyridine at different positions. Bipyridine conjugates of polyamides were found to have a high affinity for the DNA target and one of them produced a specific and high-yield cleavage in vitro and in cultured cells. The bipyridine conjugate studied here, also presents cell penetrating properties since it is active when directly added to cell culture medium. Harnessing DNA damaging molecules such as bipyridine to predetermined genomic sites, as achieved here, provides an attractive strategy for targeted genome modification and DNA repair studies.


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