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Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules
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 (DM1) is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710115/ https://www.ncbi.nlm.nih.gov/pubmed/23806903 http://dx.doi.org/10.1038/ncomms3044 |
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author | Childs-Disney, Jessica L. Stepniak-Konieczna, Ewa Tran, Tuan Yildirim, Ilyas Park, HaJeung Chen, Catherine Z. Hoskins, Jason Southall, Noel Marugan, Juan J. Patnaik, Samarjit Zheng, Wei Austin, Chris P. Schatz, George C. Sobczak, Krzysztof Thornton, Charles A. Disney, Matthew D. |
author_facet | Childs-Disney, Jessica L. Stepniak-Konieczna, Ewa Tran, Tuan Yildirim, Ilyas Park, HaJeung Chen, Catherine Z. Hoskins, Jason Southall, Noel Marugan, Juan J. Patnaik, Samarjit Zheng, Wei Austin, Chris P. Schatz, George C. Sobczak, Krzysztof Thornton, Charles A. Disney, Matthew D. |
author_sort | Childs-Disney, Jessica L. |
collection | PubMed |
description | 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 (DM1) 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. The 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 DM1. |
format | Online Article Text |
id | pubmed-3710115 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-37101152013-12-28 Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules Childs-Disney, Jessica L. Stepniak-Konieczna, Ewa Tran, Tuan Yildirim, Ilyas Park, HaJeung Chen, Catherine Z. Hoskins, Jason Southall, Noel Marugan, Juan J. Patnaik, Samarjit Zheng, Wei Austin, Chris P. Schatz, George C. Sobczak, Krzysztof Thornton, Charles A. Disney, Matthew D. Nat Commun Article 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 (DM1) 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. The 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 DM1. 2013 /pmc/articles/PMC3710115/ /pubmed/23806903 http://dx.doi.org/10.1038/ncomms3044 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Childs-Disney, Jessica L. Stepniak-Konieczna, Ewa Tran, Tuan Yildirim, Ilyas Park, HaJeung Chen, Catherine Z. Hoskins, Jason Southall, Noel Marugan, Juan J. Patnaik, Samarjit Zheng, Wei Austin, Chris P. Schatz, George C. Sobczak, Krzysztof Thornton, Charles A. Disney, Matthew D. Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules |
title | Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules |
title_full | Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules |
title_fullStr | Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules |
title_full_unstemmed | Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules |
title_short | Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules |
title_sort | induction and reversal of myotonic dystrophy type 1 pre-mrna splicing defects by small molecules |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710115/ https://www.ncbi.nlm.nih.gov/pubmed/23806903 http://dx.doi.org/10.1038/ncomms3044 |
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