4.6 Article

G-Quadruplexes Formation by the C9orf72 Nucleotide Repeat Expansion d(GGGGCC)n and Conformation Regulation by Fangchinoline

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MOLECULES
卷 28, 期 12, 页码 -

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MDPI
DOI: 10.3390/molecules28124671

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G-quadruplex; C9orf72 hexanucleotide repeat; Fangchinoline

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The G-quadruplex structures formed by C9orf72 gene play a crucial role in the pathogenesis of ALS and FTD. This study investigated the GQ structures formed by different lengths of C9-HRE DNA sequences and identified a natural small molecule, Fangchinoline, that can stabilize and alter the C9-HRE GQ structures in both DNA and RNA levels. The findings provide insights into therapeutic strategies targeting C9-HRE DNA and RNA in C9ALS/FTD.
The G-quadruplex (GQ)-forming hexanucleotide repeat expansion (HRE) in the C9orf72 (C9) gene has been found to be the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (collectively, C9ALS/FTD), implying the great significance of modulating C9-HRE GQ structures in C9ALS/FTD therapeutic treatment strategies. In this study, we investigated the GQ structures formed by varied lengths of C9-HRE DNA sequences d(GGGGCC)(4) (C9-24mer) and d(GGGGCC)(8) (C9-48mer), and found that the C9-24mer forms anti-parallel GQ (AP-GQ) in the presence of potassium ions, while the long C9-48mer bearing eight guanine tracts forms unstacked tandem GQ consisting of two C9-24mer unimolecular AP-GQs. Moreover, the natural small molecule Fangchinoline was screened out in order to be able to stabilize and alter the C9-HRE DNA to parallel GQ topology. Further study of the interaction of Fangchinoline with the C9-HRE RNA GQ unit r(GGGGCC)(4) (C9-RNA) revealed that it can also recognize and improve the thermal stability of C9-HRE RNA GQ. Finally, use of AutoDock simulation results indicated that Fangchinoline binds to the groove regions of the parallel C9-HRE GQs. These findings pave the way for further studies of GQ structures formed by pathologically related long C9-HRE sequences, and also provide a natural small-molecule ligand that modulates the structure and stability of C9-HRE GQ, both in DNA and RNA levels. Altogether, this work may contribute to therapeutic approaches of C9ALS/FTD which take the upstream C9-HRE DNA region, as well as the toxic C9-HRE RNA, as targets.

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