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Professor Panagis Filippakopoulos

Research Area: Protein Science and Structural Biology
Technology Exchange: Bioinformatics, Crystallography, Drug discovery, Mass spectrometry and Protein interaction
Scientific Themes: Cancer Biology
Keywords: Epigenetics, Transcription, Modular domains, Histones, Bromodomain, Structural biology, Drug discovery and X-ray crystallography
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Transcription in eukaryotic cells is a tightly regulated process, which depends on the spatial and transient formation of non-covalent protein complexes mediated by post-translational modifications, such as lysine acetylation. Members of the bromo and extra-terminal (BET) family play key roles in this assembly process. BET family members belong to the family of bromodomains the only known protein recognition module that selectively recognizes and binds ε-N-acetylated lysine (Kac). Dysfunction of the transcription elongation process leads to the development of aggressive cancers and disease. The specific substrates, links to cellular signalling and mode of action of these modular domains remain elusive; however their dysfunction has been linked to disease. They have been identified as oncogenic fusions in aggressive carcinomas; drive the expression of oncogenes such a c-Myc and play essential roles in viral recruitment and viral genome segregation. Importantly, we and others have demonstrated that it is possible to inhibit their function by targeting their mechanism of action resulting in dramatic effects in disease, leading to potential therapies. This novel targeting mechanism based on the inhibition of protein interactions initiated by reader domains of chromatin modifications needs to be further explored in order to understand and explain transcription initiation.

We aim to address the structural and functional role of BET bromodomains in transcription initiation and the implications of dysfunctional BET bromodomains in disease. For instance BETs are found fused to the NUT (nuclear protein in testis) protein driving the growth of a rare subtype of squamous cell carcinoma or they are associated to viral oncoproteins. We employ high throughput structural biology techniques in order to study BET bromodomains, seeking to establish an interaction map with their substrates, understand the molecular details of substrate interactions, explain synergy between multiple BET bromodomain modules, explore the molecular and structural basis for the recruitment of the positive transcription elongation factor b (P-TEFb) by BET proteins to chromatin, structurally characterize their oncogenic fusions to NUT and probe the molecular and structural basis of their interactions with viral oncoproteins.

Name Department Institution Country
Professor Anthony J Pawson FRS Medicine - Samuel Lunenfeld Research Institute University of Toronto Canada
Professor Cheryl H Arrowsmith Department of Medical Biophysics University of Toronto Canada
Dr James E Bradner Department of Medicine Dana-Farber Cencer Institute - Harvard Medical School United States
Dr George Vassiliou Department of Haematological Cancer Genetics Sanger Institute United Kingdom
Professor Olaf Wiest Chemistry and Biochemistry University of Notre Dame United States
Professor John R Engen Department of Chemistry and Chemical Biology Northeastern University United States
Professor Anne-Claude Gingras Department of Molecular Genetics University of Toronto & Samuel Lunenfeld Research Institute Canada
Professor Tom Lenaerts Department of Computer Science Université Libre de Bruxelles Belgium
Professor Shohei Koide Department of Biochemistry & Molecular Biophysics University of Chicago United States
Professor Franz Bracher Department of Pharmacy Ludwig-Maximilians-Universität München Germany
Professor Emmanuel Mikros Department of Pharmacy National and Kapodistrian University of Athens Greece
Professor Ines Bruno Department of Pharmacy University of Salerno Italy
Professor Hidenori Ichijo Department of Pharmaceutical Sciences University of Tokyo Japan
Professor Kohsuke Takeda Department of Biomedical Sciences Nagasaki University Japan
Dr John Mariadason Ludwig Cancer Research - Melbourne Branch Australia
Professor Stefan Knapp Structural Genomics Consortium University of Oxford United Kingdom
Professor Colin R Goding Oxford Ludwig Institute University of Oxford United Kingdom
Professor Nicholas La Thangue Clinical Pharnacology, Oxford University United Kingdom
Prof Sir Walter Bodmer FRS (RDM) Weatherall Institute of Molecular Medicine University of Oxford United Kingdom
Professor Tim Maughan Gray Institute for Radiation Oncology and Biology Oxford University United Kingdom

Wang CY, Filippakopoulos P. 2015. Beating the odds: BETs in disease. Trends Biochem Sci, 40 (8), pp. 468-479. Read abstract | Read more

Bromodomains (BRDs) are evolutionarily conserved protein interaction modules that specifically recognise acetyl-lysine on histones and other proteins, facilitating roles in regulating gene transcription. BRD-containing proteins bound to chromatin loci such as enhancers are often deregulated in disease leading to aberrant expression of proinflammatory cytokines and growth-promoting genes. Recent developments targeting the bromo and extraterminal (BET) subset of BRD proteins demonstrated remarkable efficacy in murine models providing a compelling rationale for drug development and translation to the clinic. Here we summarise recent advances in our understanding of the roles of BETs in regulating gene transcription in normal and diseased tissue as well as the current status of their clinical translation. Hide abstract

Filippakopoulos P, Knapp S. 2014. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov, 13 (5), pp. 337-356. Read abstract | Read more

Lysine acetylation is a key mechanism that regulates chromatin structure; aberrant acetylation levels have been linked to the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are small interaction modules found on diverse proteins, some of which have a key role in the acetylation-dependent assembly of transcriptional regulator complexes. These complexes can then initiate transcriptional programmes that result in phenotypic changes. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncology, where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addition, targeting BET bromodomains could hold potential for the treatment of inflammation and viral infection. Here, we highlight recent progress in the development of bromodomain inhibitors, and their potential applications in drug discovery. Hide abstract

Ciceri P, Müller S, O'Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA, Pallares G et al. 2014. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat Chem Biol, 10 (4), pp. 305-312. Read abstract | Read more

Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors. Hide abstract

Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M et al. 2013. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci U S A, 110 (49), pp. 19754-19759. Read abstract | Read more

Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation. Hide abstract

Picaud S, Da Costa D, Thanasopoulou A, Filippakopoulos P, Fish PV, Philpott M, Fedorov O, Brennan P et al. 2013. PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res, 73 (11), pp. 3336-3346. Read abstract | Read more

Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target. Hide abstract

Fish PV, Filippakopoulos P, Bish G, Brennan PE, Bunnage ME, Cook AS, Federov O, Gerstenberger BS et al. 2012. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J Med Chem, 55 (22), pp. 9831-9837. Read abstract | Read more

The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains. Hide abstract

Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S et al. 2012. Small-molecule inhibition of BRDT for male contraception. Cell, 150 (4), pp. 673-684. Read abstract | Read more

A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception. Hide abstract

Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R et al. 2012. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell, 149 (1), pp. 214-231. Read abstract | Read more

Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family. Hide abstract

Filippakopoulos P, Knapp S. 2012. The bromodomain interaction module FEBS Letters, 586 (17), pp. 2692-2704. Read abstract | Read more

-N-acetylation of lysine residues (K ac) is one of the most abundant post-translation modifications (PTMs) in the human proteome. In the nucleus, acetylation of histones has been linked to transcriptional activation of genes but the functional consequences of most acetylation events and proteins recruited to these sites remains largely unknown. Bromodomains (BRDs) are small helical interaction modules that specifically recognize acetylation sites in proteins. BRDs have recently emerged as interesting targets for the development of specific protein interaction inhibitors, enabling a novel exiting strategy for the development of new therapies. This review provides an overview over sequence requirements of BRDs, known substrates and the structural mechanisms of specific K ac recognition. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Hide abstract

Filippakopoulos P, Picaud S, Fedorov O, Keller M, Wrobel M, Morgenstern O, Bracher F, Knapp S. 2012. Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg Med Chem, 20 (6), pp. 1878-1886. Read abstract | Read more

Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolo-benzodiazepines have been also described as potent and highly selective protein interaction inhibitors of bromodomain and extra-terminal (BET) proteins, a family of transcriptional co-regulators that play a key role in cancer cell survival and proliferation, but the requirements for high affinity interaction of this compound class with bromodomains has not been described. Here we provide insight into the structure-activity relationship (SAR) and selectivity of this versatile scaffold. In addition, using high resolution crystal structures we compared the binding mode of a series of benzodiazepine (BzD) and related triazolo-benzotriazepines (BzT) derivatives including clinically approved drugs such as alprazolam and midazolam. Our analysis revealed the importance of the 1-methyl triazolo ring system for BET binding and suggests modifications for the development of further high affinity bromodomain inhibitors. Hide abstract

Muller S, Filippakopoulos P, Knapp S. 2011. Bromodomains as therapeutic targets. Expert Rev Mol Med, 13 pp. e29. Read abstract | Read more

Acetylation of lysine residues is a post-translational modification with broad relevance to cellular signalling and disease biology. Enzymes that 'write' (histone acetyltransferases, HATs) and 'erase' (histone deacetylases, HDACs) acetylation sites are an area of extensive research in current drug development, but very few potent inhibitors that modulate the 'reading process' mediated by acetyl lysines have been described. The principal readers of ɛ-N-acetyl lysine (K(ac)) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. The conserved BRD fold contains a deep, largely hydrophobic acetyl lysine binding site, which represents an attractive pocket for the development of small, pharmaceutically active molecules. Proteins that contain BRDs have been implicated in the development of a large variety of diseases. Recently, two highly potent and selective inhibitors that target BRDs of the BET (bromodomains and extra-terminal) family provided compelling data supporting targeting of these BRDs in inflammation and in an aggressive type of squamous cell carcinoma. It is likely that BRDs will emerge alongside HATs and HDACs as interesting targets for drug development for the large number of diseases that are caused by aberrant acetylation of lysine residues. Hide abstract

Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T et al. 2010. Selective inhibition of BET bromodomains. Nature, 468 (7327), pp. 1067-1073. Read abstract | Read more

Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family. Hide abstract

Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararajan M, Manak MS, Kwon M, Choi HG, Sim T et al. 2010. Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nat Chem Biol, 6 (5), pp. 359-368. Read abstract | Read more

Mps1, a dual-specificity kinase, is required for the proper functioning of the spindle assembly checkpoint and for the maintenance of chromosomal stability. As Mps1 function has been implicated in numerous phases of the cell cycle, the development of a potent, selective small-molecule inhibitor of Mps1 should facilitate dissection of Mps1-related biology. We describe the cellular effects and Mps1 cocrystal structures of new, selective small-molecule inhibitors of Mps1. Consistent with RNAi studies, chemical inhibition of Mps1 leads to defects in Mad1 and Mad2 establishment at unattached kinetochores, decreased Aurora B kinase activity, premature mitotic exit and gross aneuploidy, without any evidence of centrosome duplication defects. However, in U2OS cells having extra centrosomes (an abnormality found in some cancers), Mps1 inhibition increases the frequency of multipolar mitoses. Lastly, Mps1 inhibitor treatment resulted in a decrease in cancer cell viability. Hide abstract

Eswaran J, Patnaik D, Filippakopoulos P, Wang F, Stein RL, Murray JW, Higgins JM, Knapp S. 2009. Structure and functional characterization of the atypical human kinase haspin. Proc Natl Acad Sci U S A, 106 (48), pp. 20198-20203. Read abstract | Read more

The protein kinase haspin/Gsg2 plays an important role in mitosis, where it specifically phosphorylates Thr-3 in histone H3 (H3T3). Its protein sequence is only weakly homologous to other protein kinases and lacks the highly conserved motifs normally required for kinase activity. Here we report structures of human haspin in complex with ATP and the inhibitor iodotubercidin. These structures reveal a constitutively active kinase conformation, stabilized by haspin-specific inserts. Haspin also has a highly atypical activation segment well adapted for specific recognition of the basic histone tail. Despite the lack of a DFG motif, ATP binding to haspin is similar to that in classical kinases; however, the ATP gamma-phosphate forms hydrogen bonds with the conserved catalytic loop residues Asp-649 and His-651, and a His651Ala haspin mutant is inactive, suggesting a direct role for the catalytic loop in ATP recognition. Enzyme kinetic data show that haspin phosphorylates substrate peptides through a rapid equilibrium random mechanism. A detailed analysis of histone modifications in the neighborhood of H3T3 reveals that increasing methylation at Lys-4 (H3K4) strongly decreases substrate recognition, suggesting a key role of H3K4 methylation in the regulation of haspin activity. Hide abstract

Filippakopoulos P, Müller S, Knapp S. 2009. SH2 domains: modulators of nonreceptor tyrosine kinase activity. Curr Opin Struct Biol, 19 (6), pp. 643-649. Read abstract | Read more

The Src homology 2 (SH2) domain is a sequence-specific phosphotyrosine-binding module present in many signaling molecules. In cytoplasmic tyrosine kinases, the SH2 domain is located N-terminally to the catalytic kinase domain (SH1) where it mediates cellular localization, substrate recruitment, and regulation of kinase activity. Initially, structural studies established a role of the SH2 domain stabilizing the inactive state of Src family members. However, biochemical characterization showed that the presence of the SH2 domain is frequently required for catalytic activity, suggesting a crucial function stabilizing the active state of many nonreceptor tyrosine kinases. Recently, the structure of the SH2-kinase domain of Fes revealed that the SH2 domain stabilizes the active kinase conformation by direct interactions with the regulatory helix alphaC. Stabilizing interactions between the SH2 and the kinase domains have also been observed in the structures of active Csk and Abl. Interestingly, mutations in the SH2 domain found in human disease can be explained by SH2 domain destabilization or incorrect positioning of the SH2. Here we summarize our understanding of mechanisms that lead to tyrosine kinase activation by direct interactions mediated by the SH2 domain and discuss how mutations in the SH2 domain trigger kinase inactivation. Hide abstract

Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I, Savitsky P, Burgess-Brown NA, Müller S, Knapp S. 2009. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell, 136 (2), pp. 352-363. Read abstract | Read more

Protein tyrosine phosphatases (PTPs) play a critical role in regulating cellular functions by selectively dephosphorylating their substrates. Here we present 22 human PTP crystal structures that, together with prior structural knowledge, enable a comprehensive analysis of the classical PTP family. Despite their largely conserved fold, surface properties of PTPs are strikingly diverse. A potential secondary substrate-binding pocket is frequently found in phosphatases, and this has implications for both substrate recognition and development of selective inhibitors. Structural comparison identified four diverse catalytic loop (WPD) conformations and suggested a mechanism for loop closure. Enzymatic assays revealed vast differences in PTP catalytic activity and identified PTPD1, PTPD2, and HDPTP as catalytically inert protein phosphatases. We propose a "head-to-toe" dimerization model for RPTPgamma/zeta that is distinct from the "inhibitory wedge" model and that provides a molecular basis for inhibitory regulation. This phosphatome resource gives an expanded insight into intrafamily PTP diversity, catalytic activity, substrate recognition, and autoregulatory self-association. Hide abstract

Filippakopoulos P, Kofler M, Hantschel O, Gish GD, Grebien F, Salah E, Neudecker P, Kay LE et al. 2008. Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation. Cell, 134 (5), pp. 793-803. Read abstract | Read more

The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling. Hide abstract

Modular Role of the ET Domain of BET proteins in Transcription

Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT in human) belong to the class of bromodomains (BRDs), the only known protein module that selectively recognizes acetylated lysine residues found on histones and other diverse proteins (Filippakopoulos and Knapp, 2012; Filippakopoulos et al., 2012; Muller et al., 2011). BETs contain two conserved N-terminal), an extra terminal domain (ET) and a more divergent C-terminal recruitment domain (CT motif or CTM). They stimulate transcri ...

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Role of the NUT and its Fusion to BET Proteins in Cancer

Proteins of the bromo and extra terminal (BET) family are key mediators for the initiation of transcription elongation (Bres et al., 2008). Chromosomal translocations that involve BET proteins have been identified in an aggressive form of human squamous carcinoma (French et al., 2003). In these translocations the two N-terminal BET bromodomains are fused in-frame with the NUT (nuclear protein in testis) protein giving rise to the so-called NUT midline carcinoma (NMC). Functional studies in patie ...

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Structural Role of BET proteins in Transcription Initiation

Proteins of the bromo and extra terminal (BET) family are key mediators for the assembly of the positive transcription elongation factor b complex (P-TEFb), an event required for the initiation of transcription elongation (Bres et al., 2008). The P-TEFb core complex is composed of cyclin-dependent kinase-9 (CDK9) and its activator cyclin T, and it functions to activate RNA polymerase II (RNAPol-II). BET proteins (BRD2, BRD3, BRD4 and BRDT in human) contain two conserved N-terminal bromodomains ( ...

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