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Chemical probes identify a role for histone deacetylase 3 in Friedreich's ataxia gene silencing

Academic Article
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Overview

authors

  • Xu, C. P.
  • Soragni, E.
  • Chou, C. J.
  • Herman, D.
  • Plasterer, H. L.
  • Rusche, J. R.
  • Gottesfeld, Joel

publication date

  • September 2009

journal

  • Chemistry & Biology  Journal

abstract

  • We recently identified a class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease. Here, we describe chemical approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chemistry addition of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high-affinity target of the probe. Photoaffinity labeling in a nuclear extract prepared from human lymphoblasts with the trifunctional probe, followed by biotin addition through click chemistry, streptavidin enrichment, and Western blotting also identifies HDAC3 as the preferred cellular target of the inhibitor. Additional inhibitors with different HDAC specificity profiles were synthesized, and results from transcription experiments in FRDA cells point to a unique role for HDAC3 in gene silencing in Friedreich's ataxia.

subject areas

  • Animals
  • Cell Line
  • Drug Design
  • Enzyme Inhibitors
  • Friedreich Ataxia
  • Gene Silencing
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Humans
  • Iron-Binding Proteins
  • Mice
  • Neuroprotective Agents
  • Photoaffinity Labels
  • Pimelic Acids
  • Recombinant Proteins
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Identity

PubMed Central ID

  • PMC2909763

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2009.07.010

PubMed ID

  • 19778726
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Additional Document Info

start page

  • 980

end page

  • 989

volume

  • 16

issue

  • 9

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