Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Poznan, Poland.
Wiley Interdiscip Rev RNA. 2022 Jul;13(4):e1709. doi: 10.1002/wrna.1709. Epub 2022 Feb 28.
Short tandem repeats are repetitive nucleotide sequences robustly distributed in the human genome. Their expansion underlies the pathogenesis of multiple neurological disorders, including Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, fragile X-associated tremor/ataxia syndrome, and myotonic dystrophies, known as repeat expansion disorders (REDs). Several molecular pathomechanisms associated with toxic RNA containing expanded repeats (RNA ) are shared among REDs and contribute to disease progression, however, detailed mechanistic insight into those processes is limited. To deepen our understanding of the interplay between toxic RNA molecules and multiple protein partners, in this review, we discuss the roles of selected RNA-binding proteins (RBPs) that interact with RNA and thus act as "partners in crime" in the progression of REDs. We gather current findings concerning RBPs involved at different stages of the RNA life cycle, such as transcription, splicing, transport, and AUG-independent translation of expanded repeats. We argue that the activity of selected RBPs can be unique or common among REDs depending on the expanded repeat type. We also present proteins that are functionally depleted due to sequestration on RNA within nuclear foci and those which participate in RNA -dependent innate immunity activation. Moreover, we discuss the utility of selected RBPs as targets in the development of therapeutic strategies. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.
短串联重复序列是在人类基因组中广泛分布的重复核苷酸序列。它们的扩增是多种神经退行性疾病的发病机制基础，包括亨廷顿病、肌萎缩性侧索硬化症和额颞叶痴呆、脆性 X 相关震颤共济失调综合征和肌强直性营养不良症，这些疾病被称为重复扩增障碍（REDs）。几种与含有扩增重复的毒性 RNA 相关的分子病理机制在 REDs 中是共有的，并有助于疾病进展，然而，这些过程的详细机制见解是有限的。为了更深入地了解毒性 RNA 分子与多种蛋白质伴侣之间的相互作用，在这篇综述中，我们讨论了与 RNA 相互作用的选定 RNA 结合蛋白（RBPs）的作用，这些蛋白在 REDs 的进展中充当“共犯”。我们汇集了关于参与 RNA 生命周期不同阶段的 RBPs 的最新发现，例如转录、剪接、运输以及扩增重复的 AUG 非依赖性翻译。我们认为，根据扩增重复的类型，选定的 RBPs 的活性在 REDs 中可能是独特的或共同的。我们还介绍了由于 RNA 在核斑点内的隔离而在功能上被耗尽的蛋白质以及参与 RNA 依赖性先天免疫激活的蛋白质。此外，我们讨论了选定的 RBPs 作为开发治疗策略的靶标的用途。本文归类于：RNA 与蛋白质和其他分子的相互作用 > 蛋白质-RNA 相互作用：功能意义 RNA 在疾病与发育中的作用 > RNA 在疾病中。
