Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA.
The RNA Institute, Department of Biological Sciences, University at Albany, State University of New York, Albany, NY 12222, USA.
Biochim Biophys Acta Gene Regul Mech. 2019 Nov-Dec;1862(11-12):194405. doi: 10.1016/j.bbagrm.2019.07.006. Epub 2019 Jul 16.
Over 30 hereditary disorders attributed to the expansion of microsatellite repeats have been identified. Despite variant nucleotide content, number of consecutive repeats, and different locations in the genome, many of these diseases have pathogenic RNA gain-of-function mechanisms. The repeat-containing RNAs can form structures in vitro predicted to contribute to the disease through assembly of intracellular RNA aggregates termed foci. The expanded repeat RNAs within these foci sequester RNA binding proteins (RBPs) with important roles in the regulation of RNA metabolism, most notably alternative splicing (AS). These deleterious interactions lead to downstream alterations in transcriptome-wide AS directly linked with disease symptoms. This review summarizes existing knowledge about the association between the repeat RNA structures and RBPs as well as the resulting aberrant AS patterns, specifically in the context of myotonic dystrophy. The connection between toxic, structured RNAs and dysregulation of AS in other repeat expansion diseases is also discussed. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm.
已经确定了 30 多种遗传性疾病是由于微卫星重复序列的扩展引起的。尽管核苷酸组成、连续重复的数量和基因组中的位置不同，但这些疾病中的许多都具有致病性 RNA 获得功能的机制。含有重复序列的 RNA 可以在体外形成结构，通过组装称为焦点的细胞内 RNA 聚集体来预测这些结构有助于疾病。这些焦点内的扩展重复 RNA 会隔离具有重要作用的 RNA 代谢调节的 RNA 结合蛋白 (RBP)，尤其是可变剪接 (AS)。这些有害相互作用导致与疾病症状直接相关的转录组范围内 AS 的下游改变。这篇综述总结了关于重复 RNA 结构与 RBP 以及由此产生的异常 AS 模式之间的关联的现有知识，特别是在肌萎缩性侧索硬化症的背景下。还讨论了有毒、结构 RNA 与其他重复扩展疾病中 AS 失调之间的联系。本文是由 Francisco Baralle、Ravindra Singh 和 Stefan Stamm 编辑的题为“RNA 结构和剪接调控”的特刊的一部分。
