Regulation of MBD1-mediated transcriptional repression by SUMO and PIAS proteins

EMBO J. 2006 Nov 15;25(22):5317-28. doi: 10.1038/sj.emboj.7601404. Epub 2006 Oct 26.

Abstract

In mammalian cells, DNA methylation is associated with heritable and stable gene repression, mediated in part by methyl-CpG-binding domain (MBD) proteins that recruit corepressors to modify chromatin. MBD1 protein, a member of the MBD family, forms a complex with SETDB1 histone methylase to silence transcription at target promoters by methylation of lysine 9 of histone H3. How MBD1-mediated transcriptional repression is regulated is currently unknown. Here we show that MBD1 is a target for sumoylation by PIAS1 (Protein Inhibitors of Activated STAT 1) and PIAS3 E3 SUMO (small ubiquitin-like modifier)-ligases, at two conserved lysine residues within the C-terminus of MBD1. Although sumoylated MBD1 binds to methylated DNA, it does not incorporate into a complex with SETDB1 and does not efficiently repress transcription of a target gene, p53BP2, in HeLa cells. Our data suggest that transcriptional silencing by MBD1 is regulated by a PIAS-mediated conjugation of SUMO1, which antagonizes the formation of a repressive complex with SETDB1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Amino Acid Sequence
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology
  • Chromatin / genetics
  • Chromatin / physiology
  • Conserved Sequence
  • DNA Methylation
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Down-Regulation
  • Gene Silencing
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase
  • Histones / metabolism
  • Humans
  • Molecular Chaperones / genetics
  • Molecular Chaperones / physiology*
  • Molecular Sequence Data
  • Protein Binding
  • Protein Inhibitors of Activated STAT / genetics
  • Protein Inhibitors of Activated STAT / physiology*
  • Protein Methyltransferases / metabolism
  • SUMO-1 Protein
  • Sequence Homology, Amino Acid
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Small Ubiquitin-Related Modifier Proteins / physiology*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcription, Genetic*

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • MBD1 protein, human
  • Molecular Chaperones
  • PIAS1 protein, human
  • PIAS3 protein, human
  • Protein Inhibitors of Activated STAT
  • SUMO-1 Protein
  • SUMO1 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • TP53BP2 protein, human
  • Transcription Factors
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • SETDB1 protein, human