Abstract
Tandem PHD and bromodomains are often found in chromatin-associated proteins and have been shown to cooperate in gene silencing. Each domain can bind specifically modified histones: the mechanisms of cooperation between these domains are unknown. We show that the PHD domain of the KAP1 corepressor functions as an intramolecular E3 ligase for sumoylation of the adjacent bromodomain. The RING finger-like structure of the PHD domain is required for both Ubc9 binding and sumoylation and directs modification to specific lysine residues in the bromodomain. Sumoylation is required for KAP1-mediated gene silencing and functions by directly recruiting the SETDB1 histone methyltransferase and the CHD3/Mi2 component of the NuRD complex via SUMO-interacting motifs. Sumoylated KAP1 stimulates the histone methyltransferase activity of SETDB1. These data provide a mechanistic explanation for the cooperation of PHD and bromodomains in gene regulation and describe a function of the PHD domain as an intramolecular E3 SUMO ligase.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / metabolism
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Autoantigens / genetics
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Autoantigens / metabolism
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology
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Cells, Cultured
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Chromatin / metabolism
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DNA Helicases / genetics
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DNA Helicases / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation*
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Gene Silencing*
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Histone-Lysine N-Methyltransferase
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Humans
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Kidney / metabolism
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Lysine / chemistry
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Mi-2 Nucleosome Remodeling and Deacetylase Complex
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Osteosarcoma / genetics
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Osteosarcoma / metabolism
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Osteosarcoma / pathology
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Protein Methyltransferases / genetics
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Protein Methyltransferases / metabolism
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Protein Processing, Post-Translational
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RING Finger Domains*
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / growth & development
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Saccharomyces cerevisiae / metabolism
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Small Ubiquitin-Related Modifier Proteins / metabolism*
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Transcription, Genetic
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Tripartite Motif-Containing Protein 28
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Two-Hybrid System Techniques
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Ubiquitin-Conjugating Enzymes / genetics
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Ubiquitin-Conjugating Enzymes / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Autoantigens
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CHD4 protein, human
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Chromatin
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DNA-Binding Proteins
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Repressor Proteins
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Small Ubiquitin-Related Modifier Proteins
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase
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SETDB1 protein, human
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Ubiquitin-Conjugating Enzymes
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TRIM28 protein, human
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Tripartite Motif-Containing Protein 28
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Ubiquitin-Protein Ligases
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Histone Deacetylases
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Mi-2 Nucleosome Remodeling and Deacetylase Complex
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Adenosine Triphosphatases
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DNA Helicases
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CHD3 protein, human
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ubiquitin-conjugating enzyme UBC9
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Lysine