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

Authors

  • Matthew J Lyst,

    1. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
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  • Xinsheng Nan,

    1. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
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    • Present address: MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
  • Irina Stancheva

    Corresponding author
    1. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
    • Corresponding author. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Mayfield Road, Edinburgh EH9 3JR, UK. Tel.: +44 131 650 7029; Fax: +44 131 650 7360; E-mail: istancheva@ed.ac.uk

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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.

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