Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR

Wolfgang Fischle, Franck Dequiedt, Michael J. Hendzel, Matthew G. Guenther, Mitchell A. Lazar, Wolfgang Voelter, Eric Verdin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

655 Scopus citations

Abstract

Histone deacetylases (HDACs) play a key role in regulating eukaryotic gene expression. The HDAC domain, homologous to the yeast repressors RPD3 and HDA1, is considered necessary and sufficient for enzymatic activity. Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT. All experimental conditions leading to the suppression of HDAC4 binding to SMRT/N-CoR and to HDAC3 result in the loss of enzymatic activity associated with HDAC4. In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.

Original languageEnglish (US)
Pages (from-to)45-57
Number of pages13
JournalMolecular cell
Volume9
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Bibliographical note

Funding Information:
We thank John C.W. Carroll and Stephen Gonzales for graphics, Heather Gravois for manuscript preparation, Stephen Ordway and Gary Howard for editorial assistance, Drs. Warner Greene and Veronique Kiermer for helpful discussions, Darin McDonald for excellent technical assistance, and Dr. Guy Georges with help for the modeling of class II HDACs on the structure of HDLP. The National Cell Culture Center provided large-scale HeLa cell cultures. This research was supported in part by NIH grant GM51671, the International Agency for Research on Cancer, and by institutional funds from the Gladstone Institute of Virology and Immunology (E.V.) and the Medical Research Council of Canada (M.J.H.). W.F. was supported by a fellowship from the Boehringer Ingelheim Foundation, Germany. F.D. is a Postdoctoral Researcher of the Belgium National Fund of Scientific Research. M.J.H. is a Scholar of the Medical Research Council of Canada.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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