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Title: Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model

In this study, CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase ( DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein–RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Ψ or 2'-O-methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecular dynamics and X-ray crystallography suggest a potential water-bridging mechanism for Ψ-mediated CUG repeat stabilization. Ψ modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [2] ;  [1] ;  [1]
  1. Univ. of Oregon, Eugene, OR (United States)
  2. Univ. of Michigan, Ann Arbor, MI (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 42; Journal Issue: 20; Journal ID: ISSN 0305-1048
Publisher:
Oxford University Press
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1208669

deLorimier, Elaine, Coonrod, Leslie A., Copperman, Jeremy, Taber, Alex, Reister, Emily E., Sharma, Kush, Todd, Peter K., Guenza, Marina G., and Berglund, J. Andrew. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model. United States: N. p., Web. doi:10.1093/nar/gku941.
deLorimier, Elaine, Coonrod, Leslie A., Copperman, Jeremy, Taber, Alex, Reister, Emily E., Sharma, Kush, Todd, Peter K., Guenza, Marina G., & Berglund, J. Andrew. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model. United States. doi:10.1093/nar/gku941.
deLorimier, Elaine, Coonrod, Leslie A., Copperman, Jeremy, Taber, Alex, Reister, Emily E., Sharma, Kush, Todd, Peter K., Guenza, Marina G., and Berglund, J. Andrew. 2014. "Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model". United States. doi:10.1093/nar/gku941. https://www.osti.gov/servlets/purl/1208669.
@article{osti_1208669,
title = {Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model},
author = {deLorimier, Elaine and Coonrod, Leslie A. and Copperman, Jeremy and Taber, Alex and Reister, Emily E. and Sharma, Kush and Todd, Peter K. and Guenza, Marina G. and Berglund, J. Andrew},
abstractNote = {In this study, CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase (DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein–RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Ψ or 2'-O-methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecular dynamics and X-ray crystallography suggest a potential water-bridging mechanism for Ψ-mediated CUG repeat stabilization. Ψ modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases.},
doi = {10.1093/nar/gku941},
journal = {Nucleic Acids Research},
number = 20,
volume = 42,
place = {United States},
year = {2014},
month = {10}
}