Ghetu, A. F. et al. Structure of a BCOR co-repressor peptide in complex with the BCL-6 BTB domain dimer. Mol. Cell 29, 384-391

Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, 101 College Street, Toronto, ON M5G 1L7, Canada.
Molecular Cell (Impact Factor: 14.02). 03/2008; 29(3):384-91. DOI: 10.1016/j.molcel.2007.12.026
Source: PubMed


The transcriptional corepressors BCOR, SMRT, and NCoR are known to bind competitively to the BCL6 BTB domain despite the fact that BCOR has no detectable sequence similarity to the other two corepressors. We have identified a 17 residue motif from BCOR that binds directly to the BCL6 BTB domain and determined the crystal structure of the complex to a resolution of 2.6 A. Remarkably, the BCOR BCL6 binding domain (BCOR(BBD)) peptide binds in the same BCL6 binding site as the SMRT(BBD) peptide despite the lack of any significant sequence similarity between the two peptides. Mutations of critical BCOR(BBD) residues cause the disruption of the BCL6 corepression activities of BCOR, and a BCOR(BBD) peptide blocks BCL6-mediated transcriptional repression and kills lymphoma cells.

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    • "Homophenylalanine and styryl derivatives had intermediate affinities. Modelling of these artificial amino acids, such that they have the same orientation as tryptophan509 of BCOR and histidine1426 of SMRT [6], suggested explanations for this data (Figure 5B, 5C and 5D). Whilst 1-naphthyl is oriented within the pocket, 2-naphthyl clashes with the BCL6-POZ domain, which is likely to prevent significant binding. "
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    ABSTRACT: BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ∼40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor.
    PLoS ONE 03/2014; 9(3):e90889. DOI:10.1371/journal.pone.0090889 · 3.23 Impact Factor
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    • "These results suggest that recruitment of these corepressors may be just as vital for normal GC B cells as for DLBCL cells. Confirming this hypothesis, knockin mice expressing a BCL6 N21KH116A lateral groove mutant, which is unable to recruit SMRT, NCOR, and BCOR but is otherwise normally expressed, folded, and bound to target genes (Ahmad et al., 2003; Ghetu et al., 2008), fail to form GCs (Figure S3A) (Huang et al., 2013). "
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    ABSTRACT: The BCL6 transcriptional repressor is required for the development of germinal center (GC) B cells and diffuse large B cell lymphomas (DLBCLs). Although BCL6 can recruit multiple corepressors, its transcriptional repression mechanism of action in normal and malignant B cells is unknown. We find that in B cells, BCL6 mostly functions through two independent mechanisms that are collectively essential to GC formation and DLBCL, both mediated through its N-terminal BTB domain. These are (1) the formation of a unique ternary BCOR-SMRT complex at promoters, with each corepressor binding to symmetrical sites on BCL6 homodimers linked to specific epigenetic chromatin features, and (2) the "toggling" of active enhancers to a poised but not erased conformation through SMRT-dependent H3K27 deacetylation, which is mediated by HDAC3 and opposed by p300 histone acetyltransferase. Dynamic toggling of enhancers provides a basis for B cells to undergo rapid transcriptional and phenotypic changes in response to signaling or environmental cues.
    Cell Reports 07/2013; 4(3). DOI:10.1016/j.celrep.2013.06.016 · 8.36 Impact Factor
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    • "BCOR is a corepressor of several transcription factors, first discovered for its ability to inhibit BCL6 through the BCOR-BCL6 binding domain [35]. Interestingly, BCOR mutated allele was preferentially expressed, accounting for 90% of the RNA sequencing reads (Table 3). "
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    ABSTRACT: Molecular pathology of thymomas is poorly understood. Genomic aberrations are frequently identified in tumors but no extensive sequencing has been reported in thymomas. Here we present the first comprehensive view of a B3 thymoma at whole genome and transcriptome levels. A 55-year-old Caucasian female underwent complete resection of a stage IVA B3 thymoma. RNA and DNA were extracted from a snap frozen tumor sample with a fraction of cancer cells over 80%. We performed array comparative genomic hybridization using Agilent platform, transcriptome sequencing using HiSeq 2000 (Illumina) and whole genome sequencing using Complete Genomics Inc platform. Whole genome sequencing determined, in tumor and normal, the sequence of both alleles in more than 95% of the reference genome (NCBI Build 37). Copy number (CN) aberrations were comparable with those previously described for B3 thymomas, with CN gain of chromosome 1q, 5, 7 and X and CN loss of 3p, 6, 11q42.2-qter and q13. One translocation t(11;X) was identified by whole genome sequencing and confirmed by PCR and Sanger sequencing. Ten single nucleotide variations (SNVs) and 2 insertion/deletions (INDELs) were identified; these mutations resulted in non-synonymous amino acid changes or affected splicing sites. The lack of common cancer-associated mutations in this patient suggests that thymomas may evolve through mechanisms distinctive from other tumor types, and supports the rationale for additional high-throughput sequencing screens to better understand the somatic genetic architecture of thymoma.
    PLoS ONE 04/2013; 8(4):e60572. DOI:10.1371/journal.pone.0060572 · 3.23 Impact Factor
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