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

University of Minnesota Duluth, Duluth, Minnesota, United States
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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    • "This finding is consistent with a recently published analysis in which BCOR ITD was identified by RT-PCR in all the 20 CCSK tumors tested [10]. BCOR protein, namely BCL6 corepressor, was shown to specifically inhibit gene expression through its interaction with BCL6 and with specific class I and II of histone deacetylases [12]. The ITD identified in our work involved the PUFD domain of the protein, necessary for the epigenetic functions of BCOR, while maintaining the BCL6-binding domain. "
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    ABSTRACT: Purpose: Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor that is frequently difficult to distinguish among other childhood renal tumors due to its histological heterogeneity. This work evaluates genetic abnormalities carried by a series of CCSK samples by whole transcriptome sequencing (WTS), to identify molecular biomarkers that could improve the diagnostic process. Methods: WTS was performed on tumor RNA from 8 patients with CCSK. Bioinformatic analysis, with implementation of a pipeline for detection of intragenic rearrangements, was executed. Sanger sequencing and gene expression were evaluated to validate BCOR internal tandem duplication (ITD). Results: WTS did not identify any shared SNVs, Ins/Del or fusion event. Conversely, analysis of intragenic rearrangements enabled the detection of a breakpoint within BCOR transcript recurrent in all samples. Three different in-frame ITD in exon15 of BCOR, were detected. The presence of the ITD was confirmed on tumor DNA and cDNA, and resulted in overexpression of BCOR. Conclusion: WTS coupled with specific bioinformatic analysis is able to detect rare genetic events, as intragenic rearrangements. ITD in the last exon of BCOR is recurrent in all CCSK samples analyzed, representing a valuable molecular marker to improve diagnosis of this rare childhood renal tumor.
    Preview · Article · Oct 2015 · Oncotarget
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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]. "
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    ABSTRACT: Rybp (Ring1 and Yy1 Binding Protein) is a transcriptional regulator and member of the noncanonical polycomb repressive complex 1 with essential role in early embryonic development. We have previously described that alteration of Rybp dosage in mouse models induced striking neural tube defects (NTDs), exencephaly, and disorganized neurocortex. In this study we further investigated the role of Rybp in neural differentiation by utilising wild type ( r y b p + / + ) and rybp null mutant ( r y b p - / - ) embryonic stem cells (ESCs) and tried to uncover underlying molecular events that are responsible for the observed phenotypic changes. We found that rybp null mutant ESCs formed less matured neurons, astrocytes, and oligodendrocytes from existing progenitors than wild type cells. Furthermore, lack of rybp coincided with altered gene expression of key neural markers including Pax6 and Plagl1 pinpointing a possible transcriptional circuit among these genes.
    Full-text · Article · Aug 2015 · International Journal of Stem Cells
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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.
    Preview · Article · Oct 2013 · Molecular Plant
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