期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 10, 页码 5881-5890出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab302
关键词
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资金
- National Science Foundation of China [32071188, 21473150, 31670728]
- Hong Kong Special Administrative Region [16103717, 16103719, 16101120, SZSTI19SC02, SMSEGL20SC01-H, AoE/M-403-16, AoE/M-401/20]
- Natural Science Foundation of Guangdong Province [2020A1515010034]
- Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) [SMSEGL20SC01]
The hexanucleotide repeat expansion GGGGCC (G4C2) in the C9orf72 gene's first intron is a common genetic cause of ALS and FTD, forming toxic G-quadruplex structures. The study reveals the G-quadruplex structures of d(G4C2) and provides valuable details for developing small molecule drugs to treat neurodegenerative diseases.
The hexanucleotide repeat expansion, GGGGCC (G4C2), within the first intron of the C9orf72 gene is known to be the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The G4C2 repeat expansions, either DNA or RNA, are able to form G-quadruplexes which induce toxicity leading to ALS/FTD. Herein, we report a novel crystal structure of d(G4C2)(2) that self-associates to form an eight-layer parallel tetrameric G-quadruplex. Two d(G4C2)(2) associate together as a parallel dimeric G-quadruplex which folds into a tetramer via 5 '-to-5 ' arrangements. Each dimer consists of four G-tetrads connected by two CC propeller loops. Especially, the 3 '-end cytosines protrude out and form CC+center dot CC+/ CCcenter dot CC+ quadruple base pair or C center dot CC+ triple base pair stacking on the dimeric block. Our work sheds light on the G-quadruplexes adopted by d(G4C2) and yields the invaluable structural details for the development of small molecules to tackle neurodegenerative diseases, ALS and FTD.
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