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The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase.

Transcriptional repression mediated through histone deacetylation is a critical component of eukaryotic gene regulation. Here we demonstrate that the class II histone deacetylase HDAC4 is covalently modified by the ubiquitin-related SUMO-1 modifier. A sumoylation-deficient point mutant (HDAC4-K559R) shows a slightly impaired ability to repress transcription as well as reduced histone deacetylase activity. The ability of HDAC4 to self-aggregate is a prerequisite for proper sumoylation in vivo. Calcium/calmodulin-dependent protein kinase (CaMK) signalling, which induces nuclear export, abrogates SUMO-1 modification of HDAC4. Moreover, the modification depends on the presence of an intact nuclear localization signal and is catalysed by the nuclear pore complex (NPC) RanBP2 protein, a factor newly identified as a SUMO E3 ligase. These findings suggest that sumoylation of HDAC4 takes place at the NPC and is coupled to its nuclear import. Finally, modification experiments indicate that the MEF2-interacting transcription repressor (MITR) as well as HDAC1 and -6 are similarly SUMO modified, indicating that sumoylation may be an important regulatory mechanism for the control of transcriptional repression mediated by both class I and II HDACs.

Pubmed ID: 12032081


  • Kirsh O
  • Seeler JS
  • Pichler A
  • Gast A
  • Müller S
  • Miska E
  • Mathieu M
  • Harel-Bellan A
  • Kouzarides T
  • Melchior F
  • Dejean A


The EMBO journal

Publication Data

June 3, 2002

Associated Grants


Mesh Terms

  • Animals
  • Blotting, Western
  • COS Cells
  • Cell Nucleus
  • Chromatin
  • Cytoplasm
  • Dimerization
  • Electrophoresis, Polyacrylamide Gel
  • Genes, Reporter
  • Glutathione Transferase
  • HeLa Cells
  • Histone Deacetylases
  • Humans
  • Lysine
  • Microscopy, Fluorescence
  • Molecular Chaperones
  • Mutation
  • Nuclear Pore Complex Proteins
  • Plasmids
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Repressor Proteins
  • Signal Transduction
  • Transcription, Genetic
  • Transfection