PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Required for Gene Silencing

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Molecular Cell (Impact Factor: 14.02). 01/2008; 28(5):823-37. DOI: 10.1016/j.molcel.2007.11.012
Source: PubMed


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.

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    • "In human embryonic stem (hES) and mouse ES (mES) cells, the KRAB-ZFP-mediated docking of KAP1 at EREs triggers the formation of heterochromatin through the recruitment of the SETDB1 (also known as ESET) histone methyltransferase, responsible for trimethylating histone 3 at Lys9; histone deacetylases; and HP1 (heterochromatin protein 1), which collectively induce transcriptional repression (Schultz et al. 2002; Ivanov et al. 2007). The further recruitment of DNA methyltransferases (DNMTs) results in permanent silencing marks, which are subsequently maintained throughout development without need for persistent expression of sequence-specific ERErecognizing repressors (Quenneville et al. 2012; Rowe et al. 2013a). "
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    • "KRAB recruits TRIM28 and its associated partners that include chromatin modifying protein complexes. Histone deacetylation, histone methylation and local deposition of HP1 heterochromatin proteins are thought to result in the formation of heterochromatin and thus confer transcriptional repression [19]–[21]. The obvious assumption that KRAB-ZNF proteins act as transcriptional repressors through binding to the promoter regions of their target genes was substantiated in several studies (e.g. "
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