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.
| Original language | English |
|---|---|
| Article number | 2044 |
| Journal | Nature Communications |
| Volume | 4 |
| Publication status | Published - 2013 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Chemistry(all)
- Physics and Astronomy(all)
- Medicine(all)
Cite this
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.
In: Nature Communications, Vol. 4, 2044, 2013.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules.
AU - Childs-Disney, Jessica L.
AU - Stepniak-Konieczna, Ewa
AU - Tran, Tuan
AU - Yildirim, Ilyas
AU - Park, HaJeung
AU - Chen, Catherine Z.
AU - Hoskins, Jason
AU - Southall, Noel
AU - Marugan, Juan J.
AU - Patnaik, Samarjit
AU - Zheng, Wei
AU - Austin, Chris P.
AU - Schatz, George C
AU - Sobczak, Krzysztof
AU - Thornton, Charles A.
AU - Disney, Matthew D.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
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M3 - Article
C2 - 23806903
AN - SCOPUS:84889102738
VL - 4
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 2044
ER -