BCL6 evolved in vertebrates as a stress tolerance gene and is broadly used by cancer cells to adapt to stress
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69974 | GEO | 2019/11/20
REPOSITORIES: GEO
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Project description:Several lines of evidence link the canonical oncogene BCL6 to stress response. Here we demonstrate that BCL6 evolved in vertebrates as a component of the HSF1-driven stress response, which has been co-opted by the immune system to support germinal center formation and may have been decisive in the convergent evolution of humoral immunity in jawless and jawed vertebrates. We find that the highly conserved BTB corepressor binding site of BCL6 mediates stress adaptation across vertebrates. We demonstrate that pan-cancer cells hijack this stress tolerance mechanism to aberrantly express BCL6. Targeting the BCL6 BTB domain in cancer cells induces apoptosis and increases susceptibility to repeated doses of cytotoxic therapy. The chemosensitization effect upon BCL6 BTB inhibition is dependent on the derepression of TOX, implicating modulation of DNA repair as a downstream mechanism. Collectively, these data suggest a form of adaptive nononcogene addiction rooted in the natural selection of BCL6 during vertebrate evolution. SIGNIFICANCE: We demonstrate that HSF1 drives BCL6 expression to enable stress tolerance in vertebrates. We identify an HSF1-BCL6-TOX stress axis that is required by cancer cells to tolerate exposure to cytotoxic agents and points toward BCL6-targeted therapy as a way to more effectively kill a wide variety of solid tumors.This article is highlighted in the In This Issue feature, p. 565.
| S-EPMC6497559 | biostudies-literature
Project description:The transcription factor Bcl6 orchestrates the germinal center reaction through its actions in B and T cells, and regulates inflammatory signaling in macrophages. We report that genetic replacement by mutant Bcl6, which cannot bind corepressors to its BTB domain, disrupted  germinal center formation and immunoglobulin affinity maturation, due to a defect in B cell  proliferation and survival. In contrast, BTB loss of function had no effect on T follicular helper cell differentiation and function, nor other T helper subsets. Bcl6 null mice displayed a lethal inflammatory phenotype, whereas BTB mutant mice experienced normal healthy lives with no inflammation. Bcl6 repression of inflammatory responses in macrophages was accordingly independent of the BTB domain repressor function. Bcl6 thus mediates its actions through lineage-specific biochemical functions. ChIP-seq for Bcl6, SMRT and BCOR in germinal center B cells
2013-03-03 | E-GEOD-43350 | biostudies-arrayexpress
Project description:The transcription factor Bcl6 orchestrates the germinal center reaction through its actions in B and T cells, and regulates inflammatory signaling in macrophages. We report that genetic replacement by mutant Bcl6, which cannot bind corepressors to its BTB domain, disrupted germinal center formation and immunoglobulin affinity maturation, due to a defect in B cell proliferation and survival. In contrast, BTB loss of function had no effect on T follicular helper cell differentiation and function, nor other T helper subsets. Bcl6 null mice displayed a lethal inflammatory phenotype, whereas BTB mutant mice experienced normal healthy lives with no inflammation. Bcl6 repression of inflammatory responses in macrophages was accordingly independent of the BTB domain repressor function. Bcl6 thus mediates its actions through lineage-specific biochemical functions.
2013-03-03 | GSE43350 | GEO
Project description:Most small-molecule protein degraders act as interface stabilizers ‘molecular glues’ between E3 ubiquitin ligases and target proteins to induce ternary complex formation and ubiquitin-dependent target protein degradation. Here we report polymerization as a novel mechanism for small molecule-induced degradation. Using functional screens in combination with molecular and biochemical assays, we found that BI-3802, which binds to the BTB domain of the oncogenic transcription factor BCL6, induces polymerization of BCL6 into regular helical structures in vitro and foci in vivo. Polymerization precedes degradation by the SIAH1 E3 ubiquitin ligase. Hereby, a VxP amino acid motif on BCL6, distal from the drug-binding BTB domain, is required for SIAH1 binding, ubiquitination and BI-3802-induced degradation. Our findings propose that small molecule-induced polymerization is not only a new modality for targeted protein degradation, but also provides synthetic biology with a tool for tunable protein polymerization and opens new avenues for future drug design.
2020-11-20 | PXD016185 | Pride
Project description:Although BTB-zinc finger (BTB-ZF) transcription factors control the differentiation of multiple hematopoietic and immune lineages, how they function is poorly understood. The BTB-ZF factor Thpok controls intrathymic CD4+ T cell development and expression of most CD4+- and CD8+-lineage genes. Here, we identify the nucleosome remodeling and deacetylase (NuRD) complex as a novel Thpok cofactor. We locate three amino-acid residues within the Thpok BTB domain that are required for both NuRD binding and Thpok functions, and show that NuRD recruitment recapitulates the functions of the Thpok BTB domain. NuRD mediates Thpok repression of CD8+-lineage genes, including the transcription factor Runx3, but is dispensable for Cd4 expression. We show that these functions cannot be performed by the BTB domain of the Thpok-related factor Bcl6, which fails to bind NuRD. Thus, cofactor binding critically contributes to the functional specificity of BTB-zinc finger factors, which control the differentiation of most hematopoietic subsets.
2022-06-10 | GSE199739 | GEO
Project description:Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 ligases to decode the targets degradation signals, i.e., degrons. Here we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate. The entry contains the mass spectrometric raw file for the in vitro S-nitrosylation assay using NO donor NOR3.
2024-10-04 | MSV000096027 | MassIVE
Project description:Genotoxic agents remain the mainstay of cancer treatment. Unfortunately, clinical benefit is often countered by a rapid adaptive response in tumors. Here we report that the proto-oncogene BCL6 is a core component conferring tumor resistance adaption. In response to genotoxic stress, BCL6 transcription was markedly promoted in cancer cells. BCL6 upregulation was positively associated with therapy resistance and poor progression-free survival in patients. Mechanistically, we discovered that treatment of the genotoxic agent etoposide led to transcriptional reprogramming of multiple proinflammatory cytokines, among which interferon-α and interferon-γ response were significantly enriched in resistant cells. Our results further revealed that the interferon/STAT1 axis that was required for the therapeutic efficacy of etoposide directly regulated BCL6 expression. Increased BCL6 consequently activated mTOR pathway through repressing the tumor suppressor PTEN to enable cancer cell survival. Importantly, targeted inhibition of BCL6 potentiated etoposide-triggered DNA damage and apoptosis in vitro and in vivo. Collectively, our findings highlight the significance of targeting previously uncharacterized interferon-mediated BCL6 pathway to conquer tolerance of cancer cells to genotoxic stress.
2021-11-19 | GSE161803 | GEO
Project description:ZBTB17 belongs to the ZBTB (zinc finger and BTB domain protein family) family, which contains a BTB domain at the N-terminus and multiple zinc fingers at the C-terminus. In this dataset, ChIP-seq experiment was performed with anti-ZBTB17 antibody.
2024-08-20 | GSE239778 | GEO
Project description:The interaction between the transcriptional coactivators CREBBP/p300 and NCOA is governed by two intrinsically disordered domains called NCBD and CID, respectively. The CID domain emerged within the NCOA protein in deuterostome animals (including vertebrates) after their split from the protostomes (molluscs, worms, and arthropods). However, it has not been clear at which point a high affinity interaction evolved within the deuterostome clade and whether all present-day deuterostome animals have a high affinity NCBD:CID interaction. We have here expressed and measured affinity for NCBD and CID domains from animal species representing different evolutionary branches of the deuterostome tree. While all vertebrate species have high-affinity NCBD:CID interactions we found that the interaction in the echinoderm purple sea urchin is of similar affinity as that of the proposed ancestral domains. Our findings demonstrate that the high-affinity NCBD:CID interaction likely evolved in the vertebrate branch and question whether the interaction between CREBBP/p300 and NCOA is essential in nonvertebrate deuterostomes. The data provide an example of evolution of transcriptional regulation through protein-domain based inventions.
| S-EPMC7314397 | biostudies-literature
Project description:BCL6 Enables Cancer Cells to Evade Genotoxic Stress
| PRJNA679550 | ENA