Pradhan Subrata, Gao Rui, Bush Keegan, Zhang Nan, Wairkar Yogesh P, Sarkar Partha S
Department of Neurology, University of Texas Medical Branch, Galveston, TX, United States.
Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, TX, United States.
Front Cell Neurosci. 2022 Apr 4;16:837576. doi: 10.3389/fncel.2022.837576. eCollection 2022.
Emerging evidence suggests that DNA repair deficiency and genome instability may be the impending signs of many neurological diseases. Genome-wide association (GWAS) studies have established a strong correlation between genes that play a role in DNA damage repair and many neurodegenerative diseases, including Huntington's disease (HD), and several other trinucleotides repeat expansion-related hereditary ataxias. Recently, many reports have documented a significant role played by the DNA repair processes in aging and in modifying many neurodegenerative diseases, early during their progression. Studies from our lab and others have now begun to understand the mechanisms that cause defective DNA repair in HD and surprisingly, many proteins that have a strong link to known neurodegenerative diseases seem to be important players in these cellular pathways. Mutations in () gene that lead to polyglutamine repeat expansion at the N-terminal of HTT protein has been shown to disrupt transcription-coupled DNA repair process, a specialized DNA repair process associated with transcription. Due to the recent progress made in understanding the mechanisms of DNA repair in relation to HD, in this review, we will mainly focus on the mechanisms by which the wild-type huntingtin (HTT) protein helps in DNA repair during transcription, and the how polyglutamine expansions in HTT impedes this process in HD. Further studies that identify new players in DNA repair will help in our understanding of this process in neurons. Furthermore, it should help us understand how various DNA repair mechanism(s) coordinate to maintain the normal physiology of neurons, and provide insights for the development of novel drugs at prodromal stages of these neurodegenerative diseases.
新出现的证据表明，DNA修复缺陷和基因组不稳定可能是许多神经系统疾病的先兆。全基因组关联（GWAS）研究已经确定，在DNA损伤修复中起作用的基因与许多神经退行性疾病之间存在密切关联，包括亨廷顿舞蹈病（HD）以及其他几种三核苷酸重复序列扩增相关的遗传性共济失调。最近，许多报告记录了DNA修复过程在衰老以及在许多神经退行性疾病进展早期的修饰过程中所起的重要作用。我们实验室和其他机构的研究现已开始了解导致HD中DNA修复缺陷的机制，令人惊讶的是，许多与已知神经退行性疾病有密切联系的蛋白质似乎在这些细胞途径中起着重要作用。已证明导致HTT蛋白N端多聚谷氨酰胺重复序列扩增的（）基因突变会破坏转录偶联DNA修复过程，这是一种与转录相关的特殊DNA修复过程。鉴于最近在理解与HD相关的DNA修复机制方面取得的进展，在本综述中，我们将主要关注野生型亨廷顿蛋白（HTT）在转录过程中帮助DNA修复的机制，以及HTT中的多聚谷氨酰胺扩增如何在HD中阻碍这一过程。确定DNA修复中新参与者的进一步研究将有助于我们理解神经元中的这一过程。此外，它应该有助于我们了解各种DNA修复机制如何协同维持神经元的正常生理功能，并为这些神经退行性疾病前驱期新型药物的开发提供见解。
