title: Sequence-specific DNA cleavage mediated by bipyridine polyamide conjugates.
abstract: 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.
authors.affiliation: CNRS, UMR5153, Paris, F-75005, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Simon
authors.forename: Fabio
authors.initials: F
authors.lastname: Cannata
authors.forename: Loïc
authors.initials: L
authors.lastname: Perrouault
authors.forename: Ludovic
authors.initials: L
authors.lastname: Halby
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Concordet
authors.forename: Alexandre
authors.initials: A
authors.lastname: Boutorine
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ryabinin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sinyakov
authors.forename: Carine
authors.initials: C
authors.lastname: Giovannangeli
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000737:chemistry; D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D006367:HeLa Cells; D006801:Humans; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*
chemical_list: C530137:Bpy5 compound; D009757:Nylons; D011725:Pyridines; D015082:2,2'-Dipyridyl; D004247:DNA