title: Regulation of MBD1-mediated transcriptional repression by SUMO and PIAS proteins.
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.
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lyst
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Nan
authors.forename: Irina
authors.initials: I
authors.lastname: Stancheva
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002843:Chromatin / Q000235:genetics / Q000502:physiology; D017124:Conserved Sequence; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D020868:Gene Silencing; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000502:physiology*; D011496:Protein Methyltransferases / Q000378:metabolism; D025842:SUMO-1 Protein; D017386:Sequence Homology, Amino Acid; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C066141:MBD1 protein, human; D018832:Molecular Chaperones; C106529:PIAS1 protein, human; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C090468:TP53BP2 protein, human; D014157:Transcription Factors; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human