Heterogeneous migration routes of DNA triplet repeat slip-outs.
Heterogeneous migration routes of DNA triplet repeat slip-outs.
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DOI：
10.1016/j.bpr.2022.100070
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发表时间：
2022-09-14
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影响因子：
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通讯作者：
Magennis, Steven W
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文献类型：
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作者：
Bianco, Simona;Hu, Tianyu;Henrich, Oliver;Magennis, Steven W
目前尚不清楚重复DNA束的长度如何决定重复扩张性疾病的发生和发展，但由重复序列形成的二级DNA结构的动力学被认为发挥了重要作用。最近的研究表明，含有CAG或CTG重复序列的滑脱发夹和相邻双链中相邻的三联体重复序列的三向DNA连接表现出单分子FRET(SmFRET)动力学，该动力学被归因于局部构象运动和较远距离的分支迁移。在这里，我们通过对smFRET轨迹的详细动力学分析和粗粒度建模来探索这些所谓的“移动”滑出结构。尽管表面上结构简单，有六个FRET态可分辨，但大多数smFRET态表现出双指数驻留时间分布，这归因于结构的异质性和重叠的FRET态。(GAC)10重复滑出的粗粒度模拟包括对应于完整一轮分支迁移的轨迹；滑移事件之间的结构化自由能景观支持smFRET观察到的动力学复杂性。有40个CAG重复的发夹滑出，超过了几个三联体重复障碍疾病所需的重复长度，显示的smFRET停留时间平均是有10个重复的3WJ的两倍。通过分支迁移的二级结构重排相对于特定的DNA加工途径的速率可能是三重重复扩张性疾病扩大的一个重要因素。
It is unclear how the length of a repetitive DNA tract determines the onset and progression of repeat expansion diseases, but the dynamics of secondary DNA structures formed by repeat sequences are believed to play an important role. It was recently shown that three-way DNA junctions containing slip-out hairpins of CAG or CTG repeats and contiguous triplet repeats in the adjacent duplex displayed single-molecule FRET (smFRET) dynamics that were ascribed to both local conformational motions and longer-range branch migration. Here we explore these so-called "mobile" slip-out structures through a detailed kinetic analysis of smFRET trajectories and coarse-grained modeling. Despite the apparent structural simplicity, with six FRET states resolvable, most smFRET states displayed biexponential dwell-time distributions, attributed to structural heterogeneity and overlapping FRET states. Coarse-grained modeling for a (GAC)10 repeat slip-out included trajectories that corresponded to a complete round of branch migration; the structured free energy landscape between slippage events supports the dynamical complexity observed by smFRET. A hairpin slip-out with 40 CAG repeats, which is above the repeat length required for disease in several triplet repeat disorders, displayed smFRET dwell times that were on average double those of 3WJs with 10 repeats. The rate of secondary-structure rearrangement via branch migration, relative to particular DNA processing pathways, may be an important factor in the expansion of triplet repeat expansion diseases.