Solution Nuclear Magnetic Resonance Structures of ATTTT and ATTTC Pentanucleotide Repeats Associated with SCA37 and FAMEs.
Solution Nuclear Magnetic Resonance Structures of ATTTT and ATTTC Pentanucleotide Repeats Associated with SCA37 and FAMEs.
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DOI：
10.1021/acschemneuro.2c00593
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发表时间：
2022-12
影响因子：
5
通讯作者：
Jinxia Li;L. Wan;Yang Wang;Yawen Chen;H. Lee;S. L. Lam;P. Guo
中科院分区：
文献类型：
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作者：
Jinxia Li;L. Wan;Yang Wang;Yawen Chen;H. Lee;S. L. Lam;P. Guo
最近发现人类基因组中ATTTT和ATTTC五核苷酸重复序列的扩增与至少7种神经退行性疾病相关，包括脊髓小脑共济失调37型（SCA 37）和家族性成人肌阵挛性癫痫（FAME）1、2、3、4、6和7型。在某些生物过程中，非B DNA结构的形成被认为是重复扩增的一个致病因素。然而，这些富含嘧啶的ATTTT和ATTTC重复扩增的结构基础仍然难以捉摸。在这项研究中，我们研究了溶液结构的ATTTT和ATTTC重复使用核磁共振光谱。在这里，我们揭示了ATTTT和ATTTC重复可以形成一个高度紧凑的minidumbbell结构在5 '端使用其前两个重复。两个ATTTT重复序列的高分辨率结构被确定，显示出一个规则的TTTTA五环和一个准TTTT/A五环。此外，minidumbbell结构可以逃脱校对DNA聚合酶I的Klenow片段时，它位于5个或更多的碱基对远离引发位点，导致小规模的重复扩增。本工作的结果加深了我们对SCA 37和FAME中ATTTT和ATTTC重复序列扩展的理解，为合理的药物设计提供了高分辨率的结构信息。
Expansions of ATTTT and ATTTC pentanucleotide repeats in the human genome are recently found to be associated with at least seven neurodegenerative diseases, including spinocerebellar ataxia type 37 (SCA37) and familial adult myoclonic epilepsy (FAME) types 1, 2, 3, 4, 6, and 7. The formation of non-B DNA structures during some biological processes is thought as a causative factor for repeat expansions. Yet, the structural basis for these pyrimidine-rich ATTTT and ATTTC repeat expansions remains elusive. In this study, we investigated the solution structures of ATTTT and ATTTC repeats using nuclear magnetic resonance spectroscopy. Here, we reveal that ATTTT and ATTTC repeats can form a highly compact minidumbbell structure at the 5'-end using their first two repeats. The high-resolution structure of two ATTTT repeats was determined, showing a regular TTTTA pentaloop and a quasi TTTT/A pentaloop. Furthermore, the minidumbbell structure could escape from proofreading by the Klenow fragment of DNA polymerase I when it was located at five or more base pairs away from the priming site, leading to a small-scale repeat expansion. Results of this work improve our understanding of ATTTT and ATTTC repeat expansions in SCA37 and FAMEs, and provide high-resolution structural information for rational drug design.