Article

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

ABSTRACT

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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    • "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.
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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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