Two G-quadruplex structures adopted by oligonucleotide model of ALS and FTD linked GGGGCC repeats

author: Jasna Brčić, National Institute of Chemistry Slovenia
published: July 21, 2017,   recorded: May 2017,   views: 804


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The most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a large increase in the number of GGGGCC repeats located within the non-coding region of C9orf72 gene. Non-canonical structures adopted by expanded GGGGCC repeats, including G-quadruplexes, have been proposed to be crucial in pathogenesis. G-rich oligonucleotides can form in the presence of K+ or Na+ ions non-canonical four-stranded structures called G-quadruplexes, composed of stacked layers of G-quartets that are formed by four guanine residues connected by Hoogsteen hydrogen bonds. G-quadruplexes are known to be structurally diverse and their folding sensitive to oligonucleotide sequence and experimental conditions. In addition, several G-quadruplex structures often coexist in solution, representing a great challenge for high-resolution structure determination. Oligonucleotide d[(G4C2)3G4], chosen as the shortest model with the ability to fold intra-molecularly, formed two major and several minor G-quadruplex structures. Structural polymorphism was reduced by dG to 8Br-dG substitution and led to stabilization of two structures in d[(G4C2)3GGBrGG]. Interestingly, relative populations of G-quadruplex structures were sensitive to pH and rate of cooling when folding from thermally denatured state in the presence of K+ ions. Two different folding conditions were established that selectively favor formation of mostly one of the structures, thus facilitating their individual structural characterization with NMR. Two G-quadruplex structures are topologically very similar, however, they exhibit unique structures and distinct dynamic properties.

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