Evidence map›Paper›PMID 25303993›Full record

ArticleNucleic acids research2014

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.

Elaine deLorimier, Leslie A Coonrod, Jeremy Copperman, Alex Taber, Emily E Reister, Kush Sharma, Peter K Todd, Marina G Guenza, J Andrew Berglund

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nucleic acids research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed
1.5field-weighted citation impact, top 20% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

22 citing papers in PubMed, 32 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. Review
  5. Review
  6. Article
  7. Review
  8. Article
  9. Review
  10. Expanded CUG repeats inRNA (New York, N.Y.) · 2019
    Article
  11. Article
  12. Article
  13. Frontiers in neurology · 2018
    Review
  14. Article
  15. Article
  16. Review
  17. Article
  18. Article
  19. Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 1 country.

Elaine deLorimierDepartment of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.
Leslie A CoonrodDepartment of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.
Jeremy CoppermanDepartment of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.
Alex TaberDepartment of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.
Emily E ReisterDepartment of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.
Kush SharmaDepartment of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Peter K ToddDepartment of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Marina G GuenzaDepartment of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.
J Andrew BerglundDepartment of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA aberglund@molbio.uoregon.edu.
University of Oregon · USUniversity of Michigan–Ann Arbor · US

Funding

MOLECULAR BIOLOGY AND BIOPHYSICST32GM007759 · NIGMS · UNIVERSITY OF OREGON · PI NOLEN, BRADLEY J · 1985 to 2021
$8.5M
CGG repeat associated translation in Fragile X-associated Tremor/Ataxia Syndrome-Diversity SupplementR01NS086810 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI TODD, PETER K · 2014 to 2024
$4.1M
Targeting a Toxic RNA with Small MoleculesR01AR059833 · NIAMS · UNIVERSITY OF OREGON · PI BERGLUND, ANDREW · 2010 to 2014
$1.7M
Pathogenic Mechanisms in Fragile X Tremor Ataxia SyndromeK08NS069809 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI TODD, PETER K · 2010 to 2014
$877k
RNA Dominant Mechanisms in ALSI21BX001841 · VA · VETERANS HEALTH ADMINISTRATION · PI TODD, PETER K · 2014 to 2015
–
BLRD VA I21 BX001841NIAMS NIH HHS AR059833NIAMS NIH HHS R01 AR059833NIGMS NIH HHS T32 GM007759NINDS NIH HHS 1K08NS069809NINDS NIH HHS K08 NS069809NINDS NIH HHS R01 NS086810
6 · The paper itself

Abstract

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.

Indexed as

Alternative SplicingAnimalsBase Pair MismatchDisease Models, AnimalHeLa CellsHumansMethylationMyotonic DystrophyNucleic Acid ConformationPseudouridineRepetitive Sequences, Nucleic AcidRNARNA-Binding ProteinsWaterZebrafishPseudouridineRNARNA-Binding ProteinsWater

Identifiers

PMID25303993
PMCPMC4227782
OpenAlexW2125783737

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.