Small-molecule ligand induces nucleotide flipping in (CAG)n trinucleotide repeats
Small-molecule ligand induces nucleotide flipping in (CAG)n trinucleotide repeats
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DOI：
10.1038/nchembio708
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发表时间：
2005-06-01
影响因子：
14.8
通讯作者：
Kojima, C
中科院分区：
文献类型：
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作者：
Nakatani, K;Hagihara, S;Kojima, C
DNA三核苷酸重复序列，特别是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许多疾病相关，包括亨廷顿病、脊髓延髓肌萎缩和脊髓小脑共济失调（1-4）。在这些情况下，已知重复长度与发病年龄和疾病严重程度的降低相关（5，6）。（CAG）（n）、（CTG）（n）和（CGG）（n）三核苷酸的重复扩增可能与由具有X-X错配的CXG-CXG三联体组成的替代DNA发夹结构的稳定性增加有关（7-11）。选择性结合CAG重复序列的小分子配体可以为确定重复序列长度提供重要的探针，并为研究体内重复序列延伸机制提供重要的工具。在这里，我们报告说，萘啶-azaquinolone（NA，1）是CAG重复序列的配体，可用作确定重复序列长度的诊断工具。我们表明，通过NMR光谱，结合NA CAG重复诱导挤出的胞苷核苷酸从DNA螺旋。
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(1-4). In these cases, the repeat length is known to correlate with decreased age of onset and disease severity(5,6). 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(7-11). 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.