人类神经退行性疾病相关的三核苷酸重复DNA序列不稳定性机制研究进展

人类基因组内的三核苷酸重复及不稳定发生的一种分子机制

人类基因组内某些位点处的三核苷酸重复DNA序列基于不明原因出现扩增或缺失与人群中50多种神经退行性疾病的发病有关。这些三核苷酸重复DNA变得不稳定后可影响基因表达，或直接产生具有细胞毒性的RNA和蛋白质影响疾病过程。人们普遍相信疾病相关的三核苷酸重复DNA复制、修复、重组或基因转录异常可能在不稳定发生时发挥关键作用。为此，研究者利用酵母、细菌、人类细胞系等模式生物试图再现疾病相关的三核苷酸重复DNA复制、修复、重组和基因转录等情况下的不稳定过程。吕柯孬等作者结合所在课题组长期的研究积累，结合三核苷酸重复DNA序列以纯合和非纯合形式在基因组内的分布特征，首次把疾病相关三核苷酸重复DNA不稳定性类型分为碱基突变不稳定和重复单元的扩增和缺失不稳定，并以此为前提对近年来有关三核苷酸重复DNA不稳定的机制研究进行了系统分析和讨论，以助更好的理解疾病相关三核苷酸重复DNA序列不稳定性的分子机制。 

北京理工大学生命学院硕士研究生吕柯孬为本文第一作者

人类神经退行性疾病相关的三核苷酸重复DNA序列不稳定性机制研究进展

吕柯孬1   潘学峰1,2,3    

Progress on the mechanistic research of the trinucleotide repeat instabilities underlying human neurodegenerative diseases

Kenao Lv1,  Xuefeng Pan1，2，3 

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摘要/Abstract

摘要： 三核苷酸重复DNA序列扩增或缺失不稳定性与50多种人类神经退行性疾病有关。与疾病相关的三核苷酸重复拷贝数的增加或减少，影响了特定基因的表达，或因之产生具有细胞毒性的RNA和蛋白质已成为相关疾病的共有病理机制。现有的研究表明，疾病相关的三核苷酸重复拷贝数的改变有可能起因于相关三核苷酸重复DNA序列的异常DNA复制、修复、重组以及基因转录。有关人类遗传学研究也提示，发生在疾病相关的三核苷酸重复DNA部位的异常DNA复制、修复、重组或基因转录确有可能在三核苷酸重复DNA不稳定过程中发挥着关键作用。本文根据本课题组的研究经验，综述了近年来有关疾病相关三核苷酸重复不稳定性机制的研究进展，包括碱基突变不稳定、重复单元的扩增和缺失不稳定，以助更好地理解疾病相关三核苷酸重复DNA序列不稳定性的分子机制。

关键词: 三核苷酸重复, 不稳定性扩增, R-环, 非B型DNA二级结构, 神经退行性疾病

Abstract: The expansion and deletion instabilities shown by some trinucleotide repeated DNA sequences are associated with more than 50 neurodegenerative diseases in humans. The increase or decrease of the trinucleotide repeat units underlying the diseases are not yet clearly explained using any mechanism, but has been found to affect the expression of specific genes, or produces cy-totoxic RNA and protein, which has now become a common pathological mechanism of the diseases. The ongoing studies have shown that the changes in the copy numbers of the disease-related trinucleotide repeats may result from abnormal DNA replication, repair, recombination, and gene transcription. Human genetical studies also suggest that abnormal DNA replication, repair, recombination, or gene transcription that occurred in the disease-related trinucleotide repeat DNA sites may play a key role in the trinucleotide repeat DNA instabilities. Based on the research experiences of our research group, this paper reviews the recent research progress on the mechanisms of the disease-associated trinucleotide repeat DNA instabilities including their base mutation instabilities, the amplification and deletion instabilities of the repeat units, to better understand the molecular mechanism of the disease-associated trinucleotide repeats instabilities.

Key words: Trinucleotide repeats, Expansion Instability, RNA: DNA hybrids, Non-B DNA secondary structure, Neurodegenerative disease

引用本文

吕柯孬 潘学峰.

人类神经退行性疾病相关的三核苷酸重复DNA序列不稳定性机制研究进展 [J]. 遗传, doi: 10.16288/j.yczz.21-182.

Kenao Lv, Xuefeng Pan.

Progress on the mechanistic research of the trinucleotide repeat instabilities underlying human neurodegenerative diseases [J]. Hereditas(Beijing), doi: 10.16288/j.yczz.21-182.

http://www.chinagene.cn/CN/10.16288/j.yczz.21-182