Mechanism of SMRT Corepressor Recruitment by the BCL6 BTB Domain

Ahmad, Kami; Melnick, Ari; Lax, S.A.; Bouchard, Denis; Liu, Jun; Kiang, Chih-Li; Mayer, Sebastian; Takahashi, Shinichiro; Licht, Jonathan D.; Privé, Gilbert G.

doi:10.1016/s1097-2765(03)00454-4

Cited by 262 publications

(421 citation statements)

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“…Nevertheless, as discussed above, BCL6 autoregulation and differentiation-coupled control of PRDM1 expression offer two excellent model systems in which mechanistic details of BCL6-mediated transcription inhibition can be investigated in the future. Structural studies of the interaction between BCL6 and the lateral groove corepressors suggest that each BCL6 dimer can potentially bind to two such corepressors (SMRT, NCoR, and BCoR) at a time (1). Since our data indicate that BCL6 binds to CtBP1 primarily through the POZ domain with a minor contribution from RDII, it raises the question whether a BCL6 dimer already in complex with CtBP can further engage one or more of the lateral groove corepressors (which are very large proteins) and/or the RDII corepressors (HDAC2 or MTA3/NuRD) and vice versa.…”

Section: Discussionmentioning

confidence: 99%

“…Among the corepressors with well-documented in vivo functions, nuclear receptor coreceptor (NCoR), silencing mediator for retinoid and thyroid hormone receptors (SMRT), and BCL6 corepressor (BCoR) are recruited through the POZ/BTB domain while the central RDII region can interact with histone deacetylase 2 (HDAC2) and MTA3, which is a cell-type-specific component of the Mi-2/NuRD complex (8, 13-15, 19, 20, 24, 27, 49). Structural studies revealed that SMRT, NCoR, and BCoR all bind to a lateral groove in the POZ domain through a stretch of 17 amino acids (1). Using a cell-permeable BCL6 peptide inhibitor, BPI, designed to block POZ lateral groove corepressor recruitment, we have shown that SMRT/NCoR/BCoR control cell proliferation and survival in GC-derived B cells by mediating BCL6-dependent repression of genes such as ATR, TP53, and CDKN1A (32,35,37).…”

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confidence: 98%

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CtBP Is an Essential Corepressor for BCL6 Autoregulation

Mendez¹,

Polo

Yu³

et al. 2008

Molecular and Cellular Biology

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The transcription repressor BCL6 plays an essential role in the formation and function of germinal centers (GCs). While normal B cells promptly shut off BCL6 when they exit the GC, many GC-derived B-cell lymphomas sustain BCL6 expression through chromosomal translocations and activating mutations. We have previously shown that a common effect of lymphoma-associated BCL6 gene alterations is to bypass a negative autoregulatory loop that controls its transcription. In this study, we report that BCL6 autoregulation is independent of several known corepressor complexes including silencing mediator for retinoid and thyroid hormone receptors, nuclear receptor coreceptor, BCL6 corepressor, and MTA3/NuRD. Furthermore, we show that BCL6 can interact with the CtBP (C-terminal binding protein) corepressor both in vitro and in vivo and that CtBP is recruited by BCL6 to its 5 regulatory region. In lymphoma cell lines carrying BCL6 translocations, small interfering RNA-mediated CtBP knock-down selectively relieved the previously silenced wild-type BCL6 allele but not the translocated alleles, which are driven by heterologous promoters. These results demonstrate that CtBP is a novel BCL6 corepressor and suggest that a unique corepressor requirement for BCL6 autoregulation may allow GC B cells to differentially control the expression of BCL6 and other BCL6 target genes in response to environmental stimuli during the GC stage of B cell development.BCL6 is a sequence-specific transcription repressor that is required for the formation of germinal centers (GC), and its deregulated expression underlies development of many GCderived B-cell lymphomas (12,44,47). Expression of BCL6 is developmentally regulated such that in the B-cell lineage, high levels of BCL6 are restricted to the GC stage. GC are dynamic and specialized structures in the secondary lymphoid organs within which B cells undergo immunoglobulin class switch recombination and somatic hypermutation to produce diverse, high-affinity antibodies (17,26). Widely considered to be the master regulator of the GC stage of B-cell development, BCL6 maintains the GC-specific gene expression program by silencing genes involved in B-cell activation (CD69, CD80, and NF-B1), response to DNA damage (TP53 and ATR), cell-cycle regulation (CCND2, CDKN1B, and CDKN1A), and plasma cell differentiation (PRDM1) (25,29,34,37,38,40,41). Thus, neither the memory nor the plasma cell differentiation program can be initiated until expression and activity of BCL6 are extinguished by GC exit signals.BCL6 is a 95-kDa phosphoprotein with six Krüppel-type zinc fingers (ZF) at the C terminus and an N-terminal POZ/BTB domain. Our earlier work demonstrated that the maximum repression activity of BCL6 requires the entire POZ/BTB domain as well as a separate middle region, repression domain II (RDII) (7). To date, a variety of BCL6 corepressors have been described. Among the corepressors with well-documented in vivo functions, nuclear receptor coreceptor (NCoR), silencing mediator for retinoid and thyroid hormon...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

CtBP Is an Essential Corepressor for BCL6 Autoregulation

Mendez¹,

Polo

Yu³

et al. 2008

Molecular and Cellular Biology

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“…Transcription factors with a BTB domain at the N-terminus comprise a large important class of molecules involved in development and carcinogenesis. As shown in crystallographic studies, the BTB domains from PLZF (promyelocytic leukemia zinc finger), 2,3 BCL6, 4,5 LRF/ZBTB7, 6,7 Bach1, 8 and FAZF 9 are tightly interwound homodimers. In the case of Miz1, there are contradicting crystallographic data that BTB exists as either homodimer 9 or homotetramer.…”

Section: Introductionmentioning

confidence: 89%

“…[23][24][25][26] As controls, we used wellcharacterized BTB domains of human proteins Bcl6 and Miz1, which can form dimers 4 and tetramers, 10 respectively. We also examined the BTB domain of CP190, which has no significant homology to BTBs from the ttk group, and BTB from a vertebrate homolog of GAF identified recently.…”

Section: Btb Domains Of Gaf and Several Other Transcriptional Factorsmentioning

confidence: 99%

Drosophila BTB/POZ Domains of “ttk Group” Can Form Multimers and Selectively Interact with Each Other

Bonchuk

Denisov

Georgiev

et al. 2011

Journal of Molecular Biology

103

109

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Edited by M. GottesmanKeywords: GAGA; BTB domain; Mod(mdg4); CP190; chromatin insulatorThe BTB (bric-a-brac, tramtrack and broad complex)/POZ (poxvirus and zinc finger) domain is a conserved protein-protein interaction motif contained in a variety of transcription factors involved in development, chromatin remodeling, insulator activity, and carcinogenesis. All wellstudied mammalian BTB domains form obligate homodimers and, rarely, tetramers. Only the BTB domain of the Drosophila GAGA factor (GAF) has been shown to exist as higher-order multimers. The BTB domain of GAF belongs to the "ttk group" that contains several highly conserved sequences not found in other BTB domains. Here, we have shown by size-exclusion chromatography, chemical cross-linking, and nondenaturing PAGE that four additional BTB domains of the ttk group-Batman, Mod(mdg4), Pipsqueak, and Tramtrack-can form multimers, like GAF. Interestingly, the BTB domains of GAF and Batman have formed a wide range of complexes and interacted in the yeast two-hybrid assay with other BTB domains tested. In contrast, the BTB domains of Mod(mdg4), Pipsqueak, and Tramtrack have formed stable high-order multimer complexes and failed to interact with each other. The BTB domain of Drosophila CP190 protein does not belong to the ttk group. This BTB domain has formed stable dimers and has not interacted with domains of the ttk group. Previously, it was suggested that GAF oligomerization into higher-order complexes facilitates long-range activation by providing a protein bridge between an enhancer and a promoter. Unexpectedly, experiments in the Drosophila model system have not supported the role of GAF in organization of longdistance interaction between the yeast GAL4 activator and the white promoter.© 2011 Elsevier Ltd. All rights reserved. IntroductionThe BTB (bric-a-brac, tramtrack and broad complex) domain [also known as the POZ (poxvirus and zinc finger) domain] is a versatile protein-protein interaction motif that participates in a wide range of cellular functions, including transcription regulation (for review, see Ref. 1 ). Transcription factors with a BTB domain at the N-terminus comprise a large important class of molecules involved in development and carcinogenesis. As shown in crystallographic studies,

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“…Both the BTB and RD2 domain recruit distinct sets of co-repressors (Figure 1). The BCL6 BTB domain forms an obligate homodimer to create two identical and symmetrical extended lateral grooves that form docking sites for the co-repressor proteins SMRT (silencing mediator of retinoid and thyroid receptor), NCOR(nuclear receptor corepressor) and BCOR (BCL6 corepressor) (Figure 1) [36,37]. NCOR and SMRT are highly conserved scaffold/adaptor proteins, both of which can individually form a stable complex with HDAC3 (histone deacetylase 3), TBL1 (transducin-beta-like protein 1), TBLR1 (transducin-beta-like related protein 1) and GPS2 (G protein pathway suppressor 2) [38].…”

Section: Biochemical Mechanisms Of Action Of Bcl6mentioning

confidence: 99%

Mechanisms of action of BCL6 during germinal center B cell development

Huang

Melnick

2015

Sci. China Life Sci.

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The transcriptional repressor B cell lymphoma 6 (BCL6) controls a large transcriptional network that is required for the formation and maintenance of germinal centers (GC). GC B cells represent the normal counterpart of most human B-cell lymphomas, which are often characterized by deregulated BCL6 expression or BCL6-mediated pathways. BCL6 suppresses gene transcription largely through recruitment of its co-repressors through its distinct repression domain. Understanding the precise biological roles of each repression domain in normal and malignant B cells is helpful for development of targeted inhibition of BCL6 functions that is emerging as the basis for design of anti-lymphoma therapies. This review focuses on recent progress in the molecular mechanisms of action of BCL6 in B cells and discusses remaining unresolved questions related to how these mechanisms are linked to normal and malignant B cell development. BCL6, germinal center, co-repressor, lymphoma Citation:Huang CX, Melnick A. Mechanisms of action of BCL6 during germinal center B cell development.

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Mechanism of SMRT Corepressor Recruitment by the BCL6 BTB Domain

Cited by 262 publications

References 58 publications

CtBP Is an Essential Corepressor for BCL6 Autoregulation

CtBP Is an Essential Corepressor for BCL6 Autoregulation

Drosophila BTB/POZ Domains of “ttk Group” Can Form Multimers and Selectively Interact with Each Other

Mechanisms of action of BCL6 during germinal center B cell development

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