Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets

Department of Genetics, Cell Biology and Development, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2006; 26(18):6880-9. DOI: 10.1128/MCB.00630-06
Source: PubMed


The corepressor BCOR potentiates transcriptional repression by the proto-oncoprotein BCL6 and suppresses the transcriptional
activity of a common mixed-lineage leukemia fusion partner, AF9. Mutations in human BCOR cause male lethal, X-linked oculofaciocardiodental
syndrome. We identified a BCOR complex containing Polycomb group (PcG) and Skp-Cullin-F-box subcomplexes. The PcG proteins
include RING1, RYBP, NSPC1, a Posterior Sex Combs homolog, and RNF2, an E3 ligase for the mono-ubiquitylation of H2A. BCOR
complex components and mono-ubiquitylated H2A localize to BCL6 targets, indicating that the BCOR complex employs PcG proteins
to expand the repertoire of enzymatic activities that can be recruited by BCL6. This also suggests that BCL6 can target PcG
proteins to DNA. In addition, the BCOR complex contains components of a second ubiquitin E3 ligase, namely, SKP1 and FBXL10
(JHDM1B). We show that BCOR coimmunoprecipitates isoforms of FBXL10 which contain a JmjC domain that recently has been determined
to have histone H3K36 demethylase activity. The recruitment of two distinct classes of E3 ubiquitin ligases and a histone
demethylase by BCOR suggests that BCOR uses a unique combination of epigenetic modifications to direct gene silencing.

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    • "Complexes that form through these binding sites play important role in regulating cell proliferation and differentiation of multiple tissue lineages during early embryonic development. Rybp is also part of the BCOR complex (named after its BCL-6 corepressor subunit) [5], which plays important role in the differentiation of embryonic stem cells (ESCs) into ectoderm and mesoderm [6] and also is required for neurogenesis [7]. Our laboratory previously showed that Rybp is essential for early embryonic development, upregulated in certain cell types of the developing central nervous system (CNS), and that in a portion of the í µí±Ÿí µí±¦í µí±í µí± +/− mice alterations in Rybp dosage resulted in striking neural tube defects (NTDs) and disorganization of the neocortex in vivo [8]. "

    International Journal of Stem Cells 08/2015;
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    • "In addition, the mammalian Kdm2 homolog Fbxl10 binds to CpG islands through its CXXC domain and recruits the PRC1 proteins RING1B and Nspc1 to DNA in embryonic stem cells (Wu et al., 2013). Moreover, several transcription factors have been involved in the recruitment of a subset of PRC1s (Gearhart et al., 2006; Trojer et al., 2011). Therefore, the use of DNAbinding proteins to tether PRC1s to target genes may be a conserved mechanism. "
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    ABSTRACT: From mammals to plants, the Polycomb Group (PcG) machinery plays a crucial role in maintaining the repression of genes that are not required in a specific differentiation status. However, the mechanism by which PcG machinery mediates gene repression is still largely unknown in plants. Compared to animals, few PcG proteins have been identified in plants, not only because just some of these proteins are clearly conserved to their animal counterparts, but also because some PcG functions are carried out by plant-specific proteins, most of them as yet uncharacterized. For a long time, the apparent lack of Polycomb Repressive Complex (PRC)1 components in plants was interpreted according to the idea that plants, as sessile organisms, do not need a long-term repression as they must be able to respond rapidly to environmental signals; however, some PRC1 components have been recently identified, indicating that this may not be the case. Furthermore, new data regarding the recruitment of PcG complexes and maintenance of PcG repression in plants have revealed important differences to what has been reported so far. This review highlights recent progress in plant PcG function, focusing on the role of the putative PRC1 components.
    Molecular Plant 10/2013; 7(3). DOI:10.1093/mp/sst150 · 6.34 Impact Factor
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    • "BCoR is a large protein of 1721 amino acids with three ankyrin repeats but otherwise little homology to known protein sequences. It interacts with HDACs 1, 3, 4 and 5 [38] and engages in macromolecular complexes for epigenetic modifications to direct gene silencing [39]. BCoR has no DNA binding domain but is thought to function in association with transcription factors like BCL-6, AF9 or Sp1 [40,41]. "
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    ABSTRACT: Nuclear inclusions of aggregated proteins have primarily been characterized for molecules with aberrant poly-glutamine repeats and for mutated or structurally altered proteins. They were termed "nuclear aggresomes" and misfolding was shown to promote association with molecular chaperones and proteasomes. Here, we report that two components of a transcriptional repressor complex (BCL-6 and BCoR) of wildtype amino acid sequence can independently or jointly induce the formation of nuclear aggregates when overexpressed. The observation that the majority of cells rapidly downregulate BCL-6/BCoR levels, supports the notion that expression of these proteins is under tight control. The inclusions occur when BCL-6/BCoR expression exceeds 150-fold of endogenous levels. They preferentially develop in the nucleus by a gradual increase in aggregate size to form large, spheroid structures which are not associated with heat shock proteins or marked by ubiquitin. In contrast, we find the close association of BCL-6/BCoR inclusions with PML bodies and a reduction in aggregation upon the concomitant overexpression of histone deacetylases or heat shock protein 70. In summary, our data offer a perspective on nuclear aggregates distinct from classical "nuclear aggresomes": Large complexes of spheroid structure can evolve in the nucleus without being marked by the cellular machinery for protein refolding and degradation. However, nuclear proteostasis can be restored by balancing the levels of chaperones.
    PLoS ONE 10/2013; 8(10):e76845. DOI:10.1371/journal.pone.0076845 · 3.23 Impact Factor
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