Department of Physics, North Carolina State University, Raleigh, NC 27695, USA.
Department of Statistics, Florida State University, Tallahassee, FL 32306, USA.
Biomolecules. 2024 Oct 10;14(10):1278. doi: 10.3390/biom14101278.
Dynamic mutations in some human genes containing trinucleotide repeats are associated with severe neurodegenerative and neuromuscular disorders-known as Trinucleotide (or Triplet) Repeat Expansion Diseases (TREDs)-which arise when the repeat number of triplets expands beyond a critical threshold. While the mechanisms causing the DNA triplet expansion are complex and remain largely unknown, it is now recognized that the expandable repeats lead to the formation of nucleotide configurations with atypical structural characteristics that play a crucial role in TREDs. These nonstandard nucleic acid forms include single-stranded hairpins, Z-DNA, triplex structures, G-quartets and slipped-stranded duplexes. Of these, hairpin structures are the most prolific and are associated with the largest number of TREDs and have therefore been the focus of recent single-molecule FRET experiments and molecular dynamics investigations. Here, we review the structural and dynamical properties of nucleic acid hairpins that have emerged from these studies and the implications for repeat expansion mechanisms. The focus will be on CAG, GAC, CTG and GTC hairpins and their stems, their atomistic structures, their stability, and the important role played by structural interrupts.
一些含有三核苷酸重复的人类基因中的动态突变与严重的神经退行性和神经肌肉疾病有关，这些疾病被称为三核苷酸（或三联体）重复扩展疾病（TREDs），当三核苷酸重复数扩展超过临界阈值时就会发生这种疾病。虽然导致 DNA 三核苷酸扩展的机制很复杂，而且在很大程度上仍然未知，但现在人们已经认识到，可扩展的重复序列导致具有非典型结构特征的核苷酸构型的形成，这些特征在 TREDs 中起着至关重要的作用。这些非标准的核酸形式包括单链发夹、Z-DNA、三链体结构、G-四联体和滑链双链体。在这些结构中，发夹结构最为丰富，与数量最多的 TREDs 相关，因此一直是最近单分子 FRET 实验和分子动力学研究的焦点。在这里，我们回顾了这些研究中出现的核酸发夹的结构和动力学特性及其对重复扩展机制的影响。重点将放在 CAG、GAC、CTG 和 GTC 发夹及其茎上，包括它们的原子结构、稳定性，以及结构中断所起的重要作用。
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