Targeting Pathogenic DNA and RNA Repeats: A Conceptual Therapeutic Way for Repeat Expansion Diseases
Targeting Pathogenic DNA and RNA Repeats: A Conceptual Therapeutic Way for Repeat Expansion Diseases
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DOI：
10.1002/chem.202201749
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发表时间：
2022-07-18
影响因子：
4.3
通讯作者：
Han，Da
中科院分区：
文献类型：
--
作者：
Guo，Pei;Han，Da
人类基因组中短串联重复序列（STR）的扩增导致近50种神经退行性疾病，这些疾病大多是遗传性的、不可预防的和不可治愈的，对人类健康构成巨大威胁。由STR形成的非B DNA被认为是可引起重复扩增的结构中间体。随后的转录本含有扩增的RNA重复序列，可以通过形成特定的结构进一步诱导细胞毒性。直接靶向这些致病性DNA和RNA重复序列已成为治愈重复序列扩增疾病的一种新的潜在治疗策略。在这篇概念性综述中，我们首先介绍DNA和RNA结构在重复序列扩增疾病的遗传不稳定性和病理机制中的作用，然后描述DNA和RNA重复序列的结构特征，重点是通过X射线晶体学和溶液核磁共振光谱确定的三级结构，最后讨论了针对致病性DNA和RNA重复序列开发治疗重复序列扩增疾病的化学工具的最新进展和前景。
Expansions of short tandem repeats (STRs) in the human genome cause nearly 50 neurodegenerative diseases, which are mostly inheritable, nonpreventable and incurable, posing as a huge threat to human health. Non‐B DNAs formed by STRs are thought to be structural intermediates that can cause repeat expansions. The subsequent transcripts harboring expanded RNA repeats can further induce cellular toxicity through forming specific structures. Direct targeting of these pathogenic DNA and RNA repeats has emerged as a new potential therapeutic strategy to cure repeat expansion diseases. In this conceptual review, we first introduce the roles of DNA and RNA structures in the genetic instabilities and pathomechanisms of repeat expansion diseases, then describe structural features of DNA and RNA repeats with a focus on the tertiary structures determined by X‐ray crystallography and solution nuclear magnetic resonance spectroscopy, and finally discuss recent progress and perspectives of developing chemical tools that target pathogenic DNA and RNA repeats for curing repeat expansion diseases.