Characterizations of distinct parallel and antiparallel G-quadruplexes formed by two-repeat ALS and FTD related GGGGCC sequence.
Characterizations of distinct parallel and antiparallel G-quadruplexes formed by two-repeat ALS and FTD related GGGGCC sequence.
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由两次重复 ALS 和 FTD 相关 GGGGCC 序列形成的不同平行和反平行 G 四链体的表征
DOI：
10.1038/s41598-018-20852-w
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发表时间：
2018-02-05
影响因子：
4.6
通讯作者：
Zhu G
中科院分区：
文献类型：
--
作者：
Zhou B;Geng Y;Liu C;Miao H;Ren Y;Xu N;Shi X;You Y;Lee T;Zhu G
C9orf72基因GGGGCC(G4C2)重复序列的大量扩增被发现会导致毁灭性的神经系统疾病，如肌萎缩侧索硬化症(ALS)和额颞部痴呆(FTD)。C9orf72HRE DNA和RNA的结构多态可能导致转录异常，参与ALS和FTD的发生。我们发现，在钾溶液中，两个重复的G4C2 DNA d(G4C2)2同时形成平行和反平行的G-四链构象。我们用阴离子交换层析分离了d(G4C2)2的不同折叠，并用圆二色谱和核磁共振光谱对其进行了表征。平行的d(G4C2)2G-四链折叠成对称的四聚体，而反平行的d(G4C2)2采用不对称二聚体的拓扑结构。这些折叠不同于我们之前为d(G4C2)4G-四链确定的反平行椅型构象。我们的发现证明了C9orf72HRE DNA的构象异质性，并为d(G4C2)折叠提供了新的见解。同时，纯化的d(G4C2)2G-四链样品适合于进一步的三维结构表征，这是基于结构的针对ALS和FTD相关C9orf72HRE的小分子设计所必需的。
The large expansion of GGGGCC (G4C2) repeats of theC9orf72gene have been found to lead to the pathogenesis of devastating neurological diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The structural polymorphisms ofC9orf72HRE DNA and RNA may cause aberrant transcription and contribute to the development of ALS and FTD. Here we showed that the two-repeat G4C2 DNA, d(G4C2)2, simultaneously formed parallel and antiparallel G-quadruplex conformations in the potassium solution. We separated different folds of d(G4C2)2by anion exchange chromatography, followed with characterizations by circular dichroism and nuclear magnetic resonance spectroscopy. The parallel d(G4C2)2G-quadruplex folded as a symmetric tetramer, while the antiparallel d(G4C2)2adopted the topology of an asymmetric dimer. These folds are distinct from the antiparallel chair-type conformation we previously identified for the d(G4C2)4G-quadruplex. Our findings have demonstrated the conformational heterogeneity of theC9orf72HRE DNA, and provided new insights into the d(G4C2)nfolding. Meanwhile, the purified d(G4C2)2G-quadruplex samples are suitable for further three-dimensional structure characterizations, which are required for the structure-based design of small molecules targeting ALS and FTD relatedC9orf72HRE.
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C9ORF72 GGGGCC重复序列的正常等位基因长度不影响疾病表型。
影响因子：
4.2
作者：
Rutherford NJ;Heckman MG;Dejesus-Hernandez M;Baker MC;Soto-Ortolaza AI;Rayaprolu S;Stewart H;Finger E;Volkening K;Seeley WW;Hatanpaa KJ;Lomen-Hoerth C;Kertesz A;Bigio EH;Lippa C;Knopman DS;Kretzschmar HA;Neumann M;Caselli RJ;White CL 3rd;Mackenzie IR;Petersen RC;Strong MJ;Miller BL;Boeve BF;Uitti RJ;Boylan KB;Wszolek ZK;Graff-Radford NR;Dickson DW;Ross OA;Rademakers R
通讯作者：
Rademakers R
DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
DOI：
10.1016/s1474-4422(12)70043-1
发表时间：
2012-04
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Majounie E;Renton AE;Mok K;Dopper EG;Waite A;Rollinson S;Chiò A;Restagno G;Nicolaou N;Simon-Sanchez J;van Swieten JC;Abramzon Y;Johnson JO;Sendtner M;Pamphlett R;Orrell RW;Mead S;Sidle KC;Houlden H;Rohrer JD;Morrison KE;Pall H;Talbot K;Ansorge O;Chromosome 9-ALS/FTD Consortium;French research network on FTLD/FTLD/ALS;ITALSGEN Consortium;Hernandez DG;Arepalli S;Sabatelli M;Mora G;Corbo M;Giannini F;Calvo A;Englund E;Borghero G;Floris GL;Remes AM;Laaksovirta H;McCluskey L;Trojanowski JQ;Van Deerlin VM;Schellenberg GD;Nalls MA;Drory VE;Lu CS;Yeh TH;Ishiura H;Takahashi Y;Tsuji S;Le Ber I;Brice A;Drepper C;Williams N;Kirby J;Shaw P;Hardy J;Tienari PJ;Heutink P;Morris HR;Pickering-Brown S;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
2
作者：
Gray, Donald M.;Wen, Jin-Der;Fleischhauer, Joerg
通讯作者：
Fleischhauer, Joerg