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Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules

Author

Listed:
  • Jessica L. Childs-Disney

    (The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1)

  • Ewa Stepniak-Konieczna

    (Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University)

  • Tuan Tran

    (The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1
    The University at Buffalo, SUNY)

  • Ilyas Yildirim

    (Northwestern University, 2145 Sheridan Road)

  • HaJeung Park

    (The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1)

  • Catherine Z. Chen

    (NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Jason Hoskins

    (School of Medicine and Dentistry, University of Rochester)

  • Noel Southall

    (NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Juan J. Marugan

    (NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Samarjit Patnaik

    (NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Wei Zheng

    (NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health)

  • Chris P. Austin

    (NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health)

  • George C. Schatz

    (Northwestern University, 2145 Sheridan Road)

  • Krzysztof Sobczak

    (Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University)

  • Charles A. Thornton

    (School of Medicine and Dentistry, University of Rochester)

  • Matthew D. Disney

    (The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1)

Abstract

The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)exp). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)exp and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)exp. This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)exp and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.

Suggested Citation

  • Jessica L. Childs-Disney & Ewa Stepniak-Konieczna & Tuan Tran & Ilyas Yildirim & HaJeung Park & Catherine Z. Chen & Jason Hoskins & Noel Southall & Juan J. Marugan & Samarjit Patnaik & Wei Zheng & Chr, 2013. "Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3044
    DOI: 10.1038/ncomms3044
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    Cited by:

    1. Jibin Abraham Punnoose & Kevin J. Thomas & Arun Richard Chandrasekaran & Javier Vilcapoma & Andrew Hayden & Kacey Kilpatrick & Sweta Vangaveti & Alan Chen & Thomas Banco & Ken Halvorsen, 2023. "High-throughput single-molecule quantification of individual base stacking energies in nucleic acids," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Àlex L González & Jordi Teixidó & José I Borrell & Roger Estrada-Tejedor, 2016. "On the Applicability of Elastic Network Models for the Study of RNA CUG Trinucleotide Repeat Overexpansion," PLOS ONE, Public Library of Science, vol. 11(3), pages 1-20, March.

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