Polycomb Group and SCF Ubiquitin Ligases Are Found in a Novel BCOR Complex That Is Recruited to BCL6 Targets

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.The BCL6 gene encodes a sequence-specific transcriptional repressor (17, 23, 65) that is highly expressed in germinal center B cells. Germinal centers are maturation sites within lymphoid tissues where antigen-stimulated B cells proliferate, hypermutate their immunoglobulin (Ig) genes, undergo Ig class switch recombination, and give rise to progeny plasma cells that produce antibodies with high affinity for antigen (63). BCL6 plays a central role in this process, modulating the transcription of genes involved in lymphocyte activation, cell cycle arrest, apoptosis, and differentiation (5, 22, 49, 54, 59-61, 66, 75, 76). Deregulated expression of BCL6 in germinal center B cells plays an oncogenic role in non-Hodgkin's lymphomas (4, 16), presumably by inhibiting apoptosis and enhancing proliferation.BCL6 belongs to a subclass of zinc finger proteins with a POZ/BTB domain at the N terminus and Cys 2 -His 2 zinc fingers at the C terminus (3,70,87). BCL6 can interact with a variety of corepressors via several domains, including the POZ domain, a central repression domain, and the zinc fingers (19,24,25,29,36,45,82). The central domain of BCL6 recruits the corepressor MTA3 and its associated HDAC-containing chromatin remodeling complex (Mi-2/NuRD) (29). Importantly, MTA3 knockdown in B cells derepresses BCL6 targets that are upregulated upon differentiation into plasma cells (29). The POZ domain of BCL6 interacts with NCOR, SMRT, and BCOR in a mutually exclusive fashion (37). In BCL6-positive lymphoma cells, peptides that bind to the POZ domain of BCL6 and block interactions with NCOR, SMRT, and BCOR cause apoptosis and cell cycle arrest. The peptides do not, however, cause plasma cell differentiation (61). This suggests that the functions of BCL6 may be segregated among different corepr...

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

“…The identification of RAD21 in the screen in ZR-75-1 cells suggests that its overexpression may accelerate the cell cycle and prevent anti-estrogen-induced apoptotic events. F-box proteins function as components of SCF-type E3 ubiquitin ligase complexes and may participate in co-repressor complexes (Gearhart et al 2006). The presence of a histone demethylase activity in FBXL10 was shown to be important for regulation of cell senescence and transcription of rRNAs (Jin et al 2004, Takeuchi et al 2006, Frescas et al 2007, He et al 2008, Pfau et al 2008, Yamagishi et al 2008.…”

Characterization of Bcor expression in mouse development

“…In germinal center B cells, BCOR is found with BCL6 at several known BCL6 target genes, including regulators of cell proliferation and apoptosis (Gearhart et al, 2006). BCOR co-purifies with an 800 kDa complex comprised of Polycomb group transcriptional repressor proteins and SCF ubiquitin E3 ligase components (Gearhart et al, 2006).…”

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

“…Biochemical analyses identified BCOR as a complex comprising ring finger protein 2 (RFN2)/ring finger protein 1B (RING1B), polycomb group ring finger 1 (PCGF1)/nervous system polycomb 1 (NSPC1), lysine-specific demethylase 2B (KDM2B)/ F-box and leucine-rich repeat protein 10 (FBXL10), BCOR-like 1 (BCORL1), Ring 1 and YY1 binding protein (RYBP), YY1-associated factor 2 (YAF2), and S phase kinaseassociated protein 1 (SKP1; refs. [2][3][4]. The BCOR complex components are similar to the polycomb repressive complex 1 (PRC1) components ( Fig.…”

“…2A, upper lane). However, BCOR mutations tended to accumulate on the C-terminal side of the protein, which contains critical domains that recruit the main components PCGF1/NSPC1 and KDM2B (2,15). Finally, frameshift or nonsense mutations in BCOR have been also reported in 9.5% patients with retinoblastoma (22) and 3.3% patients with medulloblastoma (ref.…”