Anti-sense DNA d(GGCCCC)n expansions in C9ORF72 form i-motifs and protonated hairpins.
Anti-sense DNA d(GGCCCC)n expansions in C9ORF72 form i-motifs and protonated hairpins.
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DOI：
10.1038/srep17944
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发表时间：
2015-12-03
影响因子：
4.6
通讯作者：
Rogelj B
中科院分区：
文献类型：
--
作者：
Kovanda A;Zalar M;Šket P;Plavec J;Rogelj B
C9ORF72 中的 G4C2 六核苷酸重复扩展突变 (HREM) 代表与肌萎缩侧索硬化症 (ALS) 和额颞叶变性 (FTLD) 相关的最常见突变。迄今为止，已提出三种主要的疾病机制：C9ORF72 单倍体不足、RNA 毒性和二肽重复蛋白的积累。 HREM 的纯 GC 含量可能能够形成各种非 B DNA 结构，例如 G-四链体和 i-基序。这些结构被认为充当影响周围区域的复制、转录和翻译的启动子和调节元件。 G-四链体已在富含 G 的有义 DNA 和 RNA 链 (G4C2)n 上显示，反义 (G2C4)n 链的结构仍未解决。类似的富含C的序列可以在酸性条件下形成由两个平行双链体组成的i-基序，该双链体以头尾方向由半质子化的C+-C对保持在一起。我们表明，即使在接近生理条件下，d(G2C4)n 重复也确实形成 i 基序和质子化发夹。即使有义链存在，i-基序也仍然存在，而不是形成 DNA 双链体。与双链 DNA 相比，G-四链体和 i-基序/发夹结构的这种优先形成可能解释了 HREM 复制和转录的不稳定性。此外，i-基序/发夹可以代表 C9ORF72 相关 ALS 和 FTLD 的新药理学靶点。
The G4C2 hexanucleotide repeat expansion mutation (HREM) in C9ORF72, represents the most common mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Three main disease mechanisms have been proposed to date: C9ORF72 haploinsufficiency, RNA toxicity, and accumulation of dipeptide repeat proteins. Pure GC content of the HREM potentially enables the formation of various non-B DNA structures such as G-quadruplexes and i-motifs. These structures are proposed to act as promoters and regulatory elements affecting replication, transcription and translation of the surrounding region. G-quadruplexes have already been shown on the G-rich sense DNA and RNA strands (G4C2)n, the structure of the anti-sense (G2C4)n strand remains unresolved. Similar C-rich sequences may, under acidic conditions, form i-motifs consisting of two parallel duplexes in a head to tail orientation held together by hemi-protonated C+-C pairs. We show that d(G2C4)n repeats do form i-motif and protonated hairpins even under near-physiological conditions. Rather than forming a DNA duplex, i-motifs persist even in the presence of the sense strand. This preferential formation of G-quadruplex and i-motif/hairpin structures over duplex DNA, may explain HREM replicational and transcriptional instability. Furthermore, i-motifs/hairpins can represent a novel pharmacological target for C9ORF72 associated ALS and FTLD.