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Structural Insights Reveal the Dynamics of the Repeating r(CAG) Transcript Found in Huntington's Disease (HD) and Spinocerebellar Ataxias (SCAs).

Tawani A, Kumar A
PLoS One 10 e0131788 (2015)
Cited: 18 times
EuropePMC logo PMID: 26148061

Abstract

In humans, neurodegenerative disorders such as Huntington's disease (HD) and many spinocerebellar ataxias (SCAs) have been found to be associated with CAG trinucleotide repeat expansion. An important RNA-mediated mechanism that causes these diseases involves the binding of the splicing regulator protein MBNL1 (Muscleblind-like 1 protein) to expanded r(CAG) repeats. Moreover, mutant huntingtin protein translated from expanded r(CAG) also yields toxic effects. To discern the role of mutant RNA in these diseases, it is essential to gather information about its structure. Detailed insight into the different structures and conformations adopted by these mutant transcripts is vital for developing therapeutics targeting them. Here, we report the crystal structure of an RNA model with a r(CAG) motif, which is complemented by an NMR-based solution structure obtained from restrained Molecular Dynamics (rMD) simulation studies. Crystal structure data of the RNA model resolved at 2.3 Å reveals non-canonical pairing of adenine in 5´-CAG/3´-GAC motif samples in different syn and anti conformations. The overall RNA structure has helical parameters intermediate to the A- and B-forms of nucleic acids due to the global widening of major grooves and base-pair preferences near internal AA loops. The comprehension of structural behaviour by studying the spectral features and the dynamics also supports the flexible nature of the r(CAG) motif.

Articles - 2ms5 mentioned but not cited (3)

  1. Discovery of a potent small molecule inhibiting Huntington's disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein. Khan E, Mishra SK, Mishra R, Mishra A, Kumar A. Sci Rep 9 16872 (2019)
  2. Structural Insights Reveal the Dynamics of the Repeating r(CAG) Transcript Found in Huntington's Disease (HD) and Spinocerebellar Ataxias (SCAs). Tawani A, Kumar A. PLoS One 10 e0131788 (2015)
  3. Refining the RNA Force Field with Small-Angle X-ray Scattering of Helix-Junction-Helix RNA. He W, Naleem N, Kleiman D, Kirmizialtin S. J Phys Chem Lett 13 3400-3408 (2022)


Reviews citing this publication (4)

  1. Structural Characteristics of Simple RNA Repeats Associated with Disease and their Deleterious Protein Interactions. Ciesiolka A, Jazurek M, Drazkowska K, Krzyzosiak WJ. Front Cell Neurosci 11 97 (2017)
  2. Alternative Splicing of ALS Genes: Misregulation and Potential Therapies. Perrone B, La Cognata V, Sprovieri T, Ungaro C, Conforti FL, Andò S, Cavallaro S. Cell Mol Neurobiol 40 1-14 (2020)
  3. Structures of RNA repeats associated with neurological diseases. Błaszczyk L, Rypniewski W, Kiliszek A. Wiley Interdiscip Rev RNA 8 (2017)
  4. Exploring the Potential of Small Molecule-Based Therapeutic Approaches for Targeting Trinucleotide Repeat Disorders. Verma AK, Khan E, Bhagwat SR, Kumar A. Mol Neurobiol 57 566-584 (2020)

Articles citing this publication (11)

  1. Dynamics of strand slippage in DNA hairpins formed by CAG repeats: roles of sequence parity and trinucleotide interrupts. Xu P, Pan F, Roland C, Sagui C, Weninger K. Nucleic Acids Res 48 2232-2245 (2020)
  2. Why are Hoogsteen base pairs energetically disfavored in A-RNA compared to B-DNA? Rangadurai A, Zhou H, Merriman DK, Meiser N, Liu B, Shi H, Szymanski ES, Al-Hashimi HM. Nucleic Acids Res 46 11099-11114 (2018)
  3. Structure and Dynamics of DNA and RNA Double Helices of CAG and GAC Trinucleotide Repeats. Pan F, Man VH, Roland C, Sagui C. Biophys J 113 19-36 (2017)
  4. Design of Bivalent Nucleic Acid Ligands for Recognition of RNA-Repeated Expansion Associated with Huntington's Disease. Thadke SA, Perera JDR, Hridya VM, Bhatt K, Shaikh AY, Hsieh WC, Chen M, Gayathri C, Gil RR, Rule GS, Mukherjee A, Thornton CA, Ly DH. Biochemistry 57 2094-2108 (2018)
  5. A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases. Zhang Q, Yang M, Sørensen KK, Madsen CS, Boesen JT, An Y, Peng SH, Wei Y, Wang Q, Jensen KJ, Zuo Z, Chan HYE, Ngo JCK. Sci Rep 7 12077 (2017)
  6. Atypical structures of GAA/TTC trinucleotide repeats underlying Friedreich's ataxia: DNA triplexes and RNA/DNA hybrids. Zhang J, Fakharzadeh A, Pan F, Roland C, Sagui C. Nucleic Acids Res 48 9899-9917 (2020)
  7. RNA Toxicity and Perturbation of rRNA Processing in Spinocerebellar Ataxia Type 2. Li PP, Moulick R, Feng H, Sun X, Arbez N, Jin J, Marque LO, Hedglen E, Chan HYE, Ross CA, Pulst SM, Margolis RL, Woodson S, Rudnicki DD. Mov Disord 36 2519-2529 (2021)
  8. Conformational flexibility in the RNA stem-loop structures formed by CAG repeats. Guo P, Chan HYE, Lam SL. FEBS Lett 591 1752-1760 (2017)
  9. Molecular insights into the interaction of CAG trinucleotide RNA repeats with nucleolin and its implication in polyglutamine diseases. An Y, Chen ZS, Chan HYE, Ngo JCK. Nucleic Acids Res 50 7655-7668 (2022)
  10. Small Molecule Screening Discovers Compounds that Reduce FMRpolyG Protein Aggregates and Splicing Defect Toxicity in Fragile X-Associated Tremor/Ataxia Syndrome. Verma AK, Khan E, Mishra SK, Kumar A. Mol Neurobiol 59 1992-2007 (2022)
  11. Binding of small molecule inhibitors to RNA polymerase-Spt5 complex impacts RNA and DNA stability. Gallardo A, Dutagaci B. J Comput Aided Mol Des 38 1 (2023)


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