Zn2+ selectively stabilizes FdU-substituted DNA through a unique major groove binding motif |
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Authors: | Ghosh Supratim Salsbury Freddie R Horita David A Gmeiner William H |
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Affiliation: | 1Department of Cancer Biology, 2Program in Molecular Genetics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, 3Department of Physics, Wake Forest University, Winston-Salem, NC 27109 and 4Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA |
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Abstract: | We report, based on semi-empirical calculations, that Zn(2+) binds duplex DNA containing consecutive FdU-dA base pairs in the major groove with distorted trigonal bipyramidal geometry. In this previously uncharacterized binding motif, O4 and F5 on consecutive FdU are axial ligands while three water molecules complete the coordination sphere. NMR spectroscopy confirmed Zn(2+) complexation occurred with maintenance of base pairing while a slight hypsochromic shift in circular dichroism (CD) spectra indicated moderate structural distortion relative to B-form DNA. Zn(2+) complexation inhibited ethidium bromide (EtBr) intercalation and stabilized FdU-substituted duplex DNA (ΔT(m) > 15 °C). Mg(2+) neither inhibited EtBr complexation nor had as strong of a stabilizing effect. DNA sequences that did not contain consecutive FdU were not stabilized by Zn(2+). A lipofectamine preparation of the Zn(2+)-DNA complex displayed enhanced cytotoxicity toward prostate cancer cells relative to the individual components prepared as lipofectamine complexes indicating the potential utility of Zn(2+)-DNA complexes for cancer treatment. |
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