Nakatani Kazuhiko, Hagihara Shinya, Goto Yuki, Kobori Akio, Hagihara Masaki, Hayashi Gosuke, Kyo Motoki, Nomura Makoto, Mishima Masaki, Kojima Chojiro
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
Nat Chem Biol. 2005 Jun;1(1):39-43. doi: 10.1038/nchembio708. Epub 2005 May 24.
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.
DNA三核苷酸重复序列，尤其是CXG，在人类基因组中很常见。然而，三核苷酸重复序列的扩增与多种疾病相关，包括亨廷顿病、脊髓延髓肌萎缩症和脊髓小脑共济失调。在这些病例中，已知重复长度与发病年龄降低和疾病严重程度相关。(CAG)n、(CTG)n和(CGG)n三核苷酸的重复扩增可能与由带有X-X错配的CXG-CXG三联体组成的替代性DNA发夹结构的稳定性增加有关。选择性结合CAG重复序列的小分子配体可为确定重复长度提供重要探针，并为研究体内重复序列延伸机制提供重要工具。在此我们报告，萘啶氮杂喹诺酮（NA，1）是一种CAG重复序列的配体，可作为确定重复长度的诊断工具。我们通过核磁共振光谱表明，NA与CAG重复序列的结合会导致胞嘧啶核苷酸从DNA螺旋中挤出。
