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Inhibition of non-ATG translational events in cells via covalent small molecules targeting RNA

Academic Article
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Overview

related to degree

  • Wilson, Henry, Ph.D. in Biophysics, Scripps Research 2013 - 2019

authors

  • Yang, W. Y.
  • Wilson, Henry
  • Velagapudi, S. P.
  • Disney, Matthew

publication date

  • April 2015

journal

  • Journal of the American Chemical Society  Journal

abstract

  • One major class of disease-causing RNAs is expanded repeating transcripts. These RNAs cause diseases via multiple mechanisms, including: (i) gain-of-function, in which repeating RNAs bind and sequester proteins involved in RNA biogenesis and (ii) repeat associated non-ATG (RAN) translation, in which repeating transcripts are translated into toxic proteins without use of a canonical, AUG, start codon. Herein, we develop and study chemical probes that bind and react with an expanded r(CGG) repeat (r(CGG)(exp)) present in a 5' untranslated region that causes fragile X-associated tremor/ataxia syndrome (FXTAS). Reactive compounds bind to r(CGG)(exp) in cellulo as shown with Chem-CLIP-Map, an approach to map small molecule binding sites within RNAs in cells. Compounds also potently improve FXTAS-associated pre-mRNA splicing and RAN translational defects, while not affecting translation of the downstream open reading frame. In contrast, oligonucleotides affect both RAN and canonical translation when they bind to r(CGG)(exp), which is mechanistically traced to a decrease in polysome loading. Thus, designer small molecules that react with RNA targets can be used to profile the RNAs to which they bind in cells, including identification of binding sites, and can modulate several aspects of RNA-mediated disease pathology in a manner that may be more beneficial than oligonucleotides.

subject areas

  • Animals
  • Ataxia
  • Biotin
  • COS Cells
  • Cercopithecus aethiops
  • Fragile X Syndrome
  • Humans
  • Polyribosomes
  • Protein Biosynthesis
  • RNA
  • RNA Precursors
  • RNA Splicing
  • Small Molecule Libraries
  • Tremor
  • Trinucleotide Repeat Expansion
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Identity

PubMed Central ID

  • PMC4856029

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja507448y

PubMed ID

  • 25825793
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Additional Document Info

start page

  • 5336

end page

  • 5345

volume

  • 137

issue

  • 16

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