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: 5.04). 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.

Download full-text


Available from: Joseph A Wamstad, Aug 12, 2015
  • Source
    • "Therefore, KDM2B exists as part of a variant PRC1 complex in mouse embryonic stem cells. This observation is in agreement with recent work in cancer cell lines that identified KDM2B as part of a similar variant PRC1 complex (Gearhart et al., 2006; Sánchez et al., 2007; Gao et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: CpG islands (CGIs) are associated with most mammalian gene promoters. A subset of CGIs act as polycomb response elements (PREs) and are recognized by the polycomb silencing systems to regulate expression of genes involved in early development. How CGIs function mechanistically as nucleation sites for polycomb repressive complexes remains unknown. Here we discover that KDM2B (FBXL10) specifically recognizes non-methylated DNA in CGIs and recruits the polycomb repressive complex 1 (PRC1). This contributes to histone H2A lysine 119 ubiquitylation (H2AK119ub1) and gene repression. Unexpectedly, we also find that CGIs are occupied by low levels of PRC1 throughout the genome, suggesting that the KDM2B-PRC1 complex may sample CGI-associated genes for susceptibility to polycomb-mediated silencing. These observations demonstrate an unexpected and direct link between recognition of CGIs by KDM2B and targeting of the polycomb repressive system. This provides the basis for a new model describing the functionality of CGIs as mammalian PREs. DOI:
    eLife Sciences 12/2012; 1:e00205. DOI:10.7554/eLife.00205 · 8.52 Impact Factor
  • Source
    • "H2Aub occupation is more frequently correlated with gene silencing, while H2Bub is mostly associated with transcription activation. H2A ubiquitin ligases were found in transcription repressor complexes, such as the PRC1, BCoR,, and 2A-HUB complexes (Ogawa et al., 2002; Wang et al., 2004; Cao et al., 2005; Gearhart et al., 2006; Zhou et al., 2008). RING1B mediated H2Aub is required for polycomb targeted gene silencing (Cao et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histone post-transcriptional modifications play essential roles in regulation of all DNA related processes. Among them, histone ubiquitination has been discovered for more than three decades. However, its functions are still less well understood than other histone modifications such as methylation and acetylation. In this review, we will summarize our current understanding of histone ubiquitination and deubiquitination. In particular, we will focus on how they are regulated by histone ubiquitin ligases and deubiquitinating enzymes. We will then discuss the roles of histone ubiquitination in transcription and DNA damage response and the crosstalk between histone ubiquitination and other histone modifications. Finally, we will review the important roles of histone ubiquitination in stem cell biology and cancer.
    Frontiers in Oncology 03/2012; 2:26. DOI:10.3389/fonc.2012.00026
  • Source
    • "For example, MAX and MGA are associated with a subset of PRC1.6 complexes and they may recruit PRC1.6 to some target genes. In the case of PRC1.1, it is likely that BCL6 binding to target sequences may recruit a subset of PRC1.1 through the interaction of BcoR or BcoRL1 with BCL6 (Gearhart et al., 2006). Another potential mechanism for PRC1 recruitment is via RYBP/ YAF2-YY1 interactions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The heterogeneous nature of mammalian PRC1 complexes has hindered our understanding of their biological functions. Here, we present a comprehensive proteomic and genomic analysis that uncovered six major groups of PRC1 complexes, each containing a distinct PCGF subunit, a RING1A/B ubiquitin ligase, and a unique set of associated polypeptides. These PRC1 complexes differ in their genomic localization, and only a small subset colocalize with H3K27me3. Further biochemical dissection revealed that the six PCGF-RING1A/B combinations form multiple complexes through association with RYBP or its homolog YAF2, which prevents the incorporation of other canonical PRC1 subunits, such as CBX, PHC, and SCM. Although both RYBP/YAF2- and CBX/PHC/SCM-containing complexes compact chromatin, only RYBP stimulates the activity of RING1B toward H2AK119ub1, suggesting a central role in PRC1 function. Knockdown of RYBP in embryonic stem cells compromised their ability to form embryoid bodies, likely because of defects in cell proliferation and maintenance of H2AK119ub1 levels.
    Molecular cell 02/2012; 45(3):344-56. DOI:10.1016/j.molcel.2012.01.002 · 14.46 Impact Factor
Show more