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Structures of RNA repeats associated with neurological diseases

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All RNA molecules possess a ‘propensity’ to fold into complex secondary and tertiary structures. Although they are composed of only four types of nucleotides, they show an enormous structural richness which reflects their diverse functions in the cell. However, in some cases the folding of RNA can have deleterious consequences. Aberrantly expanded, repeated RNA sequences can exhibit gain‐of‐function abnormalities and become pathogenic, giving rise to many incurable neurological diseases. Most RNA repeats form long hairpin structures whose stem consists of noncanonical base pairs interspersed among Watson–Crick pairs. The expanded hairpins have an ability to sequester important proteins and form insoluble nuclear foci. The RNA pathology, common to many repeat disorders, has drawn attention to the structures of the RNA repeats. In this review, we summarize secondary structure probing and crystallographic studies of disease‐related RNA repeat sequences. We discuss the unique structural features which can contribute to the pathogenic properties of the repeated runs. In addition, we present the newest reports concerning structural data linked to therapeutic approaches. WIREs RNA 2017, 8:e1412. doi: 10.1002/wrna.1412

The noncanonical Ψ‐U pair inserted into CUG repeats (a) and T‐T pair found in a PNA‐PNA duplex (b). Comparison of the overall structure of a mixed RNA–PNA duplex against RNA–RNA and PNA‐PNA (c). Red sphere is a water molecule. The presented base pairs and helices were derived from the following PDB entries: (a) code 4PCJ, (b) code 5EMG, (c) code 3GLP, 5EME, 5EMG.
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All the crystallized RNA repeats fold into the A‐RNA form. The presence of G‐G cWH and A‐A cis Watson–Crick/Watson–Crick pair (cWW) pairs is accompanied by unwinding of the helix and widening of the major groove. The helix of CCUG repeats is bent and twisted, which amounts to supercoiling. The presented helices were derived from the following PDB entries: 3R1C, 3NJ6, 4E59, 4E48, 5EW4, 4XW1.
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Noncanonical U‐U cWW (a) and C‐C cWW (b) base pairs in the structure of AUUCU repeats. H‐bonds are indicated as they were interpreted by the authors. The 2 F o F c electron density map (blue) is contoured at 1σ level. The presented base pairs were derived from PDB entry 5BTM (resolution 2.78 Å, R/R free = 17.6/22.4%).
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The A‐A cis Watson–Crick/Watson–Crick pair (cWW) wobble pair at atomic resolution (a) and in lower resolution structures analyzed by Yildrim et al. (b, d, f) and Tawani and Kumar (c, e, g). On the left is a secondary structure of the crystallized duplex containing CAG repeats (green) and flanking sequences (gray). The 2F oF c electron density map (blue) is contoured at 1σ level. Red spheres are water molecules. The presented base pairs were derived from the following PDB entries: (a) code 3NJ6 (resolution 0.95 Å, R/R free = 10.6%/NA), (b, d, f) code 4J50 (resolution 1.65 Å, R/R free = 16.9/18.0%), (c, e, g) code 4YN6 (resolution 2.3 Å, R/R free = 21.7/26.1%).
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The Watson–Crick G‐C (a) and noncanonical U‐U pairs (b–d). The G‐C pair interacts by three hydrogen bonds (dashed lines). The distance between the C1′‐C1′ atoms (black line) and the λ angle are indicated. In the CUG repeats most of the U‐U pairs form the stretched U‐U cis Watson–Crick/Watson–Crick pair (cWW) wobble with one hydrogen bond (b). U‐U cWW pairs with zero (c) or two H‐bonds (d) have also been observed. The 2F oF c electron density map is light blue, contoured at 1σ level. Red spheres are water molecules. The presented base pairs were derived from the following PDB entries: (b) code 3GLP (resolution 1.23 Å, R/R free = 14.7/18.4%), (c) code 4E48 (resolution 2.5 Å, R/R free = 20.3/27.9%), (d) code 4FNJ (resolution 1.95 Å, R/R free = 20.8/26.6%).
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Effect of interruptions on the structure of CNG repeats. (a) CAG repeats in ATXN1 mRNA, (b) CAG repeats in ATXN2 mRNA, (c) CGG repeats in FMR1 mRNA. The CNG repeats are depicted in green, flanking sequences in gray. Orange letters represent the interruptions. Brackets denote the number of CNG repeats used in secondary structure probing experiments. Secondary structures were generated using RNA structure and VARNA software.
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In several CNG‐containing transcripts, flanking sequences revealed no contribution to folding and stability of the hairpin structure, and the structures show strand slippage. (a) CUG repeats in DMPK mRNA, (b) CAG repeats in ATXN2 mRNA, (c) CAG repeats in ATN1 mRNA, (d) CAG repeats in ATXN3 mRNA. In each panel, alternative structural arrangement of CNG hairpin is shown. CNG repeats are depicted in green while flanking sequences in gray. Brackets denote the number of CNG repeats used in secondary structure probing experiments. Secondary structures were generated using RNAstructure and VARNA software.
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Stabilization effect of flanking sequences on hairpin structures formed by CNG repeats. (a) CAG repeats in CACNA1A mRNA, (b) CAG repeats in ATXN1 mRNA, (c) CGG repeats in FMR1 mRNA, (d) CAG repeats in AR mRNA, (e and f) CAG repeats in HTT mRNA. Three secondary structures are shown: (e) Reprinted with permission from Ref . Copyright 2011 Oxford University Press (f) Reprinted with permission from Ref . Copyright 2013 Oxford University Press. CNG repeats are depicted in green while flanking sequences in gray. Adjacent CUG repeats in AR mRNA and CCG repeats in HTT mRNA are orange. Brackets denote the number of CNG repeats used in secondary structure probing experiments. Secondary structures were generated using RNAstructure and VARNA software.
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C‐U cis Watson–Crick/Watson–Crick pair (cWW) pairs observed in CCUG repeats analyzed by Childs‐Disney et al. (a and b) and Rypniewski et al. (c). Standard and tautomeric or protonated forms within the C–U pairs are shown on panel d. Water molecules (red spheres) are located in the minor groove. Distance in Å between the O2 atoms is indicated in panel b. The 2F oF c electron density map (blue) is contoured at 1σ level. Red spheres are water molecules. The presented base pairs were derived from the following PDB entries: (a, b) code 4K27 (resolution 2.35 Å, R/R free = 19.4/24.0%), (c) code 4XW1 (resolution 2.3 Å, R/R free = 19.1/21.3%).
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Noncanonical C‐C cis Watson–Crick/Watson–Crick pair (cWW) pairs observed in CCG (a‐c) and CCCCGG repeats (d and e). The C‐C pairs in the CCCCGG repeats show a large variety of conformation, the number of hydrogen bonds and values of the λ angles and C1′‐C1′ distance (d). One of the noncanonical C‐C pairs forms a bifurcated H‐bond (e). The 2F oF c electron density map (blue) is contoured at 1σ level. The presented base pairs were derived from the following PDB entries: (a, c) code 4E58 (resolution 1.95 Å, R/R free = 25.8/30.1%), (b) code 4E59 (resolution 1.54 Å, R/R free = 25.5/30.3%), (e) code 5EW4 (resolution 1.47 Å, R/R free = 21.5/23.9%).
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G‐G cWH pairs interacting with a sulfate anion (a) or with a Ca2+ cation (b) bound in the major groove. In G(syn) the O5′‐C5′ bond is flipped (purple) (c). The 2F oF c electron density map (blue) is contoured at 1σ level. Red spheres are water molecules. The presented base pairs were derived from the following PDB entries: (a) code 3R1C (resolution 2.05 Å, R/R free = 23.2/27.0%), (b) code 3R1D (resolution 0.97 Å, R/R free = 13.7%/NA).
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(a) Base pair arrangements in RNA repeats (green) used in structural studies. Hairpin stems consist of noncanonical base pairs flanked by canonical Watson–Crick pairs. In the case of CNG repeats N denotes one of the four natural nucleotides (A, C, U, or G). The GGGGCC repeats show an alternative quadruplex structure. (b) Constructs used in crystallographic studies. In most cases, the crystallized RNA were oligomers composed of pure repeats (left). To facilitate crystallization, flanking sequences (gray) have been added in some cases (middle) or RNA repeats were crystallized as a part of GAAA tetraloop/receptor (right, gray). Secondary structures were generated using RNA structure and VARNA software.
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