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. 2015 Nov 13:5:16673.
doi: 10.1038/srep16673.

Topology of a G-quadruplex DNA formed by C9orf72 hexanucleotide repeats associated with ALS and FTD

Bo Zhou  1 , Changdong Liu  1 , Yanyan Geng  1 , Guang Zhu  1
Affiliations

Topology of a G-quadruplex DNA formed by C9orf72 hexanucleotide repeats associated with ALS and FTD

Bo Zhou et al. Sci Rep. .

Abstract

Abnormal expansions of an intronic hexanucleotide GGGGCC (G4C2) repeat of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies suggested that the C9orf72 hexanucleotide repeat expansion (HRE), either as DNA or the transcribed RNA, can fold into G-quadruplexes with distinct structures. These structural polymorphisms lead to abortive transcripts and contribute to the pathogenesis of ALS and FTD. Using circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy, we analyzed the structures of C9orf72 HRE DNA with various G4C2 repeats. They exhibited diverse G-quadruplex folds in potassium ions. Furthermore, we determined the topology of a G-quadruplex formed by d(G4C2)4. It favors a monomeric fold and forms a chair-type G-quadruplex with a four-layer antiparallel G-tetra core and three edgewise loops, which is distinct from known structures of chair-type G-quadruplexes. Our findings highlight the conformational heterogeneity of C9orf72 HRE DNA, and may lay the necessary structural basis for designing small molecules for the modulation of ALS/FTD pathogenesis.

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Figures

Figure 1
Figure 1. C9orf72 HRE G4C2 DNAs form complex G-quadruplex structures.
(a) CD spectra of d(G4C2)G4, d(G4C2)2, d(G4C2)3, d(G4C2)4 and d(G4C2)5. (b) The imino region of 1D 1 H spectra of various DNA samples.
Figure 2
Figure 2. Imino proton (H1) assignments from 15N-filtered experiments.
The imino region of 1D 1H NMR spectra with the assignment of guanine bases in d(G4C2)4 being indicated over the reference spectrum on top. Guanine imino protons were assigned using 1D 15N-filtered HSQC spectra of samples containing site-specific low-enrichment (2%) 15N-labelled oligonucleotides at the indicated positions.
Figure 3
Figure 3. Topology determination for the C9orf72 HRE DNA d(G4C2)4.
(a) The NOESY spectrum (300 ms mixing time) showing H1–H8 connectivity. (b) Characteristic guanine H1–H8 NOE connectivity patterns around a Gα•Gβ•Gγ•Gδ tetrad as indicated by arrows. (c) Guanine H1–H8 NOE connectivities observed for the G1•G10•G13•G22, G2•G9•G14•G21, G3•G8•G15•G20 and G4•G7•G16•G19 tetrads. (d) Topology of d(G4C2)4. Anti guanines are colored in cyan, while syn guanines are colored in magenta. The backbones of the core and loops are colored in black and red, respectively.
See this image and copyright information in PMC

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