Pathogenic C9ORF72 Antisense Repeat RNA Forms a Double Helix with Tandem C:C Mismatches
Pathogenic C9ORF72 Antisense Repeat RNA Forms a Double Helix with Tandem C:C Mismatches
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DOI：
10.1021/acs.biochem.6b00136
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发表时间：
2016-03-08
期刊：
影响因子：
2.9
通讯作者：
Gagnon, Keith T.
中科院分区：
文献类型：
--
作者：
Dodd, David W.;Tomchick, Diana R.;Gagnon, Keith T.
C9 ORF 72基因第一内含子中GGGGCC/CCCCGG重复序列的扩增是额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）的主要原因。在这种称为c9 FTD/ALS的联合疾病中，扩增被双向转录成与疾病相关的正义和反义重复RNA。为了更好地理解C9 ORF 72重复RNA在分子疾病病理学中的作用，我们确定了[（CCCCGG）（3）（CCCC）]模型反义重复RNA的晶体结构，分辨率为1.47埃。RNA结构是一个A型双螺旋，由重复和规则间隔的串联C：C错配对组成，这些错配对扰乱了螺旋几何形状和表面电荷。溶液研究表明，随着重复数量的增加，优先选择A型样螺旋构象。结果为合理化重复RNA对c9 FTD/ALS分子疾病机制的贡献以及开发靶向C9 ORF 72重复RNA作为潜在治疗剂的分子提供了结构起点。
Expansion of a GGGGCC/CCCCGG repeat sequence in the first intron of the C9ORF72 gene is a leading cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this combined disorder, called c9FTD/ALS, the expansion is bidirectionally transcribed into sense and antisense repeat RNA associated with disease. To better understand the role of C9ORF72 repeat RNA in molecular disease pathology, we determined crystal structures of a [(CCCCGG)(3)(CCCC)] model antisense repeat RNA to 1.47 angstrom resolution. The RNA structure was an A-form-like double helix composed of repeating and regularly spaced tandem C:C mismatch pairs that perturbed helical geometry and surface charge. Solution studies revealed a preference for A-form-like helical conformations as the repeat number increased. Results provide a structural starting point for rationalizing the contribution of repeat RNA to c9FTD/ALS molecular disease mechanisms and for developing molecules to target C9ORF72 repeat RNA as potential therapeutics.