title: Small-molecule ligand induces nucleotide flipping in (CAG)n trinucleotide repeats.
abstract: DNA trinucleotide repeats, particularly CXG, are common within the human genome. However, expansion of trinucleotide repeats is associated with a number of disorders, including Huntington disease, spinobulbar muscular atrophy and spinocerebellar ataxia. In these cases, the repeat length is known to correlate with decreased age of onset and disease severity. Repeat expansion of (CAG)n, (CTG)n and (CGG)n trinucleotides may be related to the increased stability of alternative DNA hairpin structures consisting of CXG-CXG triads with X-X mismatches. Small-molecule ligands that selectively bound to CAG repeats could provide an important probe for determining repeat length and an important tool for investigating the in vivo repeat extension mechanism. Here we report that napthyridine-azaquinolone (NA, 1) is a ligand for CAG repeats and can be used as a diagnostic tool for determining repeat length. We show by NMR spectroscopy that binding of NA to CAG repeats induces the extrusion of a cytidine nucleotide from the DNA helix.
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan. nakatani@sanken.osaka-u.ac.jp
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakatani
authors.forename: Shinya
authors.initials: S
authors.lastname: Hagihara
authors.forename: Yuki
authors.initials: Y
authors.lastname: Goto
authors.forename: Akio
authors.initials: A
authors.lastname: Kobori
authors.forename: Masaki
authors.initials: M
authors.lastname: Hagihara
authors.forename: Gosuke
authors.initials: G
authors.lastname: Hayashi
authors.forename: Motoki
authors.initials: M
authors.lastname: Kyo
authors.forename: Makoto
authors.initials: M
authors.lastname: Nomura
authors.forename: Masaki
authors.initials: M
authors.lastname: Mishima
authors.forename: Chojiro
authors.initials: C
authors.lastname: Kojima
mesh_terms: D004247:DNA / Q000737:chemistry*; D008958:Models, Molecular; D015335:Molecular Probes / Q000737:chemistry*; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D015363:Quinolones / Q000737:chemistry*; D019680:Trinucleotide Repeat Expansion
chemical_list: D015335:Molecular Probes; D009287:Naphthyridines; D015363:Quinolones; D004247:DNA