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Small molecule recognition and tools to study modulation of r(CGG)(exp) in fragile X-associated tremor ataxia syndrome

Academic Article
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Overview

authors

  • Yang, W. Y.
  • He, F.
  • Strack, R. L.
  • Oh, S. Y.
  • Frazer, M.
  • Jaffrey, S. R.
  • Todd, P. K.
  • Disney, Matthew

publication date

  • September 2016

journal

  • ACS Chemical Biology  Journal

abstract

  • RNA transcripts containing expanded nucleotide repeats cause many incurable diseases via various mechanisms. One such disorder, fragile X-associated tremor ataxia syndrome (FXTAS), is caused by a noncoding r(CGG) repeat expansion (r(CGG)(exp)) that (i) sequesters proteins involved in RNA metabolism in nuclear foci, causing dysregulation of alternative pre-mRNA splicing, and (ii) undergoes repeat associated non-ATG translation (RANT), which produces toxic homopolymeric proteins without using a start codon. Here, we describe the design of two small molecules that inhibit both modes of toxicity and the implementation of various tools to study perturbation of these cellular events. Competitive Chemical Cross Linking and Isolation by Pull Down (C-Chem-CLIP) established that compounds bind r(CGG)(exp) and defined small molecule occupancy of r(CGG)(exp) in cells, the first approach to do so. Using an RNA GFP mimic, r(CGG)(exp)-Spinach2, we observe that our optimal designed compound binds r(CGG)(exp) and affects RNA localization by disrupting preformed RNA foci. These events correlate with an improvement of pre-mRNA splicing defects caused by RNA gain of function. In addition, the compounds reduced levels of toxic homopolymeric proteins formed via RANT. Polysome profiling studies showed that small molecules decreased loading of polysomes onto r(CGG)(exp), explaining decreased translation.
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Identity

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/acschembio.6b00147

PubMed ID

  • 27276216
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Additional Document Info

start page

  • 2456

end page

  • 2465

volume

  • 11

issue

  • 9

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