封面图片
2016年, 第10卷 第2期
(Jasna Brčić, Janez Plavec, pp. 222-237)
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative diseases with devastating consequences. Largely increased number of GGGGCC repeats located within the first intron of C9orf72 gene was identified as the most frequent genetic cause of ALS and FTD. It was proposed that G-quadruplexes formed in the DNA strand of the expanded GGGGCC repeat cause transcriptional pausing and abortion, which leads to accumulation of abortive G-quadruplex forming RNA transcripts. In addition to RNA transcripts being toxic, evidence suggests that they can undergo RAN (repeat-associated non-ATG) translation producing potentially harmful dipeptide repeat proteins. Initial NMR investigation of DNA oligonucleotides with four repeat units chosen as the shortest model with the ability to form a unimolecular G-quadruplex indicated their folding into multiple G-quadruplex structures in the presence of K+ ions. We set to reduce the structural polymorphism by directing the folding towards the most stable naturally occurring G-quadruplex structure. Several approaches were used to drive a complex equilibrium, including point mutations, different folding conditions and use of conformationally constrained 8Br-dG residue. Oligonucleotide d[(G4C2)3GGBrGG] bearing a single dG to 8Br-dG substitution at position 21 formed a single G-quadruplex structure at pH 7.2, which allowed its unequivocal structure determination.
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ISSN 2095-0179 (Print)
ISSN 2095-0187 (Online)
CN 11-5981/TQ
Postal Subscription Code 80-969 Formerly Known as Frontiers of Chemical Science and Engineering in China 2018 Impact Factor: 2.809