The Bromodomain Protein BRD4 Positively Regulates Necroptosis Via Modulating MLKL Expression
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Bromodomain Factors of BET Family Are New Essential Actors Of
Bromodomain factors of BET family are new essential actors of pericentric heterochromatin transcriptional activation in response to heat shock Edwige Col, Neda Hoghoughi, Solenne Dufour, Jessica Penin, Sivan Koskas, Virginie Faure, Maria Ouzounova, Hector Hernandez-Vargash, Nicolas Reynoird, Sylvain Daujat, et al. To cite this version: Edwige Col, Neda Hoghoughi, Solenne Dufour, Jessica Penin, Sivan Koskas, et al.. Bromodomain factors of BET family are new essential actors of pericentric heterochromatin transcriptional acti- vation in response to heat shock. Scientific Reports, Nature Publishing Group, 2017, 7, pp.5418. 10.1038/s41598-017-05343-8. hal-02989794 HAL Id: hal-02989794 https://hal.archives-ouvertes.fr/hal-02989794 Submitted on 5 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. www.nature.com/scientificreports OPEN Bromodomain factors of BET family are new essential actors of pericentric heterochromatin Received: 5 August 2016 Accepted: 30 May 2017 transcriptional activation in Published: xx xx xxxx response to heat shock Edwige Col1, Neda Hoghoughi1, Solenne Dufour1, Jessica Penin1, Sivan Koskas1, Virginie Faure1, Maria Ouzounova2, Hector Hernandez-Vargash2, Nicolas Reynoird1, Sylvain Daujat4, Eric Folco1, Marc Vigneron3, Robert Schneider4,5, André Verdel1, Saadi Khochbin1, Zdenko Herceg2, Cécile Caron1 & Claire Vourc’h1 The heat shock response is characterized by the transcriptional activation of both hsp genes and noncoding and repeated satellite III DNA sequences located at pericentric heterochromatin. -
Functional Roles of Bromodomain Proteins in Cancer
cancers Review Functional Roles of Bromodomain Proteins in Cancer Samuel P. Boyson 1,2, Cong Gao 3, Kathleen Quinn 2,3, Joseph Boyd 3, Hana Paculova 3 , Seth Frietze 3,4,* and Karen C. Glass 1,2,4,* 1 Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA; [email protected] 2 Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA; [email protected] 3 Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; [email protected] (C.G.); [email protected] (J.B.); [email protected] (H.P.) 4 University of Vermont Cancer Center, Burlington, VT 05405, USA * Correspondence: [email protected] (S.F.); [email protected] (K.C.G.) Simple Summary: This review provides an in depth analysis of the role of bromodomain-containing proteins in cancer development. As readers of acetylated lysine on nucleosomal histones, bromod- omain proteins are poised to activate gene expression, and often promote cancer progression. We examined changes in gene expression patterns that are observed in bromodomain-containing proteins and associated with specific cancer types. We also mapped the protein–protein interaction network for the human bromodomain-containing proteins, discuss the cellular roles of these epigenetic regu- lators as part of nine different functional groups, and identify bromodomain-specific mechanisms in cancer development. Lastly, we summarize emerging strategies to target bromodomain proteins in cancer therapy, including those that may be essential for overcoming resistance. Overall, this review provides a timely discussion of the different mechanisms of bromodomain-containing pro- Citation: Boyson, S.P.; Gao, C.; teins in cancer, and an updated assessment of their utility as a therapeutic target for a variety of Quinn, K.; Boyd, J.; Paculova, H.; cancer subtypes. -
Histone-Binding of DPF2 Mediates Its Repressive Role in Myeloid Differentiation
Histone-binding of DPF2 mediates its repressive role in myeloid differentiation Ferdinand M. Hubera,1, Sarah M. Greenblattb,1, Andrew M. Davenporta,1, Concepcion Martinezb,YeXub,LyP.Vuc, Stephen D. Nimerb,2, and André Hoelza,2 aDivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; bSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; and cMolecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Edited by Douglas C. Rees, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, and approved April 26, 2017 (received for review January 6, 2017) Double plant homeodomain finger 2 (DPF2) is a highly evolution- RUNX1 form a methylation-dependent repressive complex in arily conserved member of the d4 protein family that is ubiqui- AML, although it remains unclear whether the two proteins bind tously expressed in human tissues and was recently shown to each other directly or act concertedly as part of a larger complex. inhibit the myeloid differentiation of hematopoietic stem/progen- Here, we present the crystal structure of the human DPF2 itor and acute myelogenous leukemia cells. Here, we present the tandem PHD finger domain at a 1.6-Å resolution. We demon- crystal structure of the tandem plant homeodomain finger domain strate that the DPF2 tandem PHD finger domain binds acetylated of human DPF2 at 1.6-Å resolution. We show that DPF2 interacts H3 and H4 histone tails, identify the primary determinants of with the acetylated tails of both histones 3 and 4 via bipartite histone recognition, and confirm these interactions in vivo. -
Function of Bromodomain and Extra-Terminal Motif Proteins (Bets) in Gata1-Mediated Transcription
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2015 Function of Bromodomain and Extra-Terminal Motif Proteins (bets) in Gata1-Mediated Transcription Aaron James Stonestrom University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Molecular Biology Commons, and the Pharmacology Commons Recommended Citation Stonestrom, Aaron James, "Function of Bromodomain and Extra-Terminal Motif Proteins (bets) in Gata1-Mediated Transcription" (2015). Publicly Accessible Penn Dissertations. 1148. https://repository.upenn.edu/edissertations/1148 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1148 For more information, please contact [email protected]. Function of Bromodomain and Extra-Terminal Motif Proteins (bets) in Gata1-Mediated Transcription Abstract Bromodomain and Extra-Terminal motif proteins (BETs) associate with acetylated histones and transcription factors. While pharmacologic inhibition of this ubiquitous protein family is an emerging therapeutic approach for neoplastic and inflammatory disease, the mechanisms through which BETs act remain largely uncharacterized. Here we explore the role of BETs in the physiologically relevant context of erythropoiesis driven by the transcription factor GATA1. First, we characterize functions of the BET family as a whole using a pharmacologic approach. We find that BETs are broadly required for GATA1-mediated transcriptional activation, but that repression is largely BET-independent. BETs support activation by facilitating both GATA1 occupancy and transcription downstream of its binding. Second, we test the specific olesr of BETs BRD2, BRD3, and BRD4 in GATA1-activated transcription. BRD2 and BRD4 are required for efficient anscriptionaltr activation by GATA1. Despite co-localizing with the great majority of GATA1 binding sites, we find that BRD3 is not equirr ed for GATA1-mediated transcriptional activation. -
Bromodomain Protein BRDT Directs ΔNp63 Function and Super
Cell Death & Differentiation (2021) 28:2207–2220 https://doi.org/10.1038/s41418-021-00751-w ARTICLE Bromodomain protein BRDT directs ΔNp63 function and super-enhancer activity in a subset of esophageal squamous cell carcinomas 1 1 2 1 1 2 Xin Wang ● Ana P. Kutschat ● Moyuru Yamada ● Evangelos Prokakis ● Patricia Böttcher ● Koji Tanaka ● 2 3 1,3 Yuichiro Doki ● Feda H. Hamdan ● Steven A. Johnsen Received: 25 August 2020 / Revised: 3 February 2021 / Accepted: 4 February 2021 / Published online: 3 March 2021 © The Author(s) 2021. This article is published with open access Abstract Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer with a particularly high prevalence in certain geographical regions and a poor prognosis with a 5-year survival rate of 15–25%. Despite numerous studies characterizing the genetic and transcriptomic landscape of ESCC, there are currently no effective targeted therapies. In this study, we used an unbiased screening approach to uncover novel molecular precision oncology targets for ESCC and identified the bromodomain and extraterminal (BET) family member bromodomain testis-specific protein (BRDT) to be 1234567890();,: 1234567890();,: uniquely expressed in a subgroup of ESCC. Experimental studies revealed that BRDT expression promotes migration but is dispensable for cell proliferation. Further mechanistic insight was gained through transcriptome analyses, which revealed that BRDT controls the expression of a subset of ΔNp63 target genes. Epigenome and genome-wide occupancy studies, combined with genome-wide chromatin interaction studies, revealed that BRDT colocalizes and interacts with ΔNp63 to drive a unique transcriptional program and modulate cell phenotype. Our data demonstrate that these genomic regions are enriched for super-enhancers that loop to critical ΔNp63 target genes related to the squamous phenotype such as KRT14, FAT2, and PTHLH. -
Structure of the Human Clamp Loader Reveals an Autoinhibited Conformation of a Substrate-Bound AAA+ Switch
Structure of the human clamp loader reveals an autoinhibited conformation of a substrate-bound AAA+ switch Christl Gaubitza,1, Xingchen Liua,b,1, Joseph Magrinoa,b, Nicholas P. Stonea, Jacob Landecka,b, Mark Hedglinc, and Brian A. Kelcha,2 aDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester MA 01605; bGraduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester MA 01605; and cDepartment of Chemistry, The Pennsylvania State University, University Park, PA 16802 Edited by Michael E. O’Donnell, HHMI and Rockefeller University, New York, NY, and approved July 27, 2020 (received for review April 20, 2020) DNA replication requires the sliding clamp, a ring-shaped protein areflexia syndrome (15), Hutchinson–Gilford progeria syn- complex that encircles DNA, where it acts as an essential cofactor drome (16), and in the replication of some viruses (17–19). It for DNA polymerases and other proteins. The sliding clamp needs is unknown whether loading by RFC contributes to PARD to be opened and installed onto DNA by a clamp loader ATPase of disease. the AAA+ family. The human clamp loader replication factor C Clamp loaders are members of the AAA+ family of ATPases (RFC) and sliding clamp proliferating cell nuclear antigen (PCNA) (ATPases associated with various cellular activities), a large are both essential and play critical roles in several diseases. De- protein family that uses the chemical energy of adenosine 5′- spite decades of study, no structure of human RFC has been re- triphosphate (ATP) to generate mechanical force (20). Most solved. Here, we report the structure of human RFC bound to AAA+ proteins form hexameric motors that use an undulating PCNA by cryogenic electron microscopy to an overall resolution ∼ spiral staircase mechanism to processively translocate a substrate of 3.4 Å. -
Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors
Author Manuscript Published OnlineFirst on February 22, 2019; DOI: 10.1158/1078-0432.CCR-18-2437 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Cooper and Patel, et al. Page 1 Overcoming BET inhibitor resistance in malignant peripheral nerve sheath tumors Jonathan M. Cooper1,6, Amish J. Patel1,2,6, Zhiguo Chen1,7, Chung-Ping Liao1,7, Kun Chen1,7, Juan Mo1, Yong Wang1, Lu Q. Le1,3,4,5 1Department of Dermatology, 2Cancer Biology Graduate Program, 3Simmons Comprehensive Cancer Center, 4UTSW Comprehensive Neurofibromatosis Clinic, 5Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, 75390-9133, USA 6Co-first authors. 7These authors contributed equally. Author for correspondence: Lu Q. Le, M.D., Ph.D. Associate Professor Department of Dermatology Simmons Comprehensive Cancer Center UT Southwestern Medical Center Phone: (214) 648-5781 Fax: (214) 648-5553 E-mail: [email protected] Running Title: Cancer cell sensitivity and resistance to BET inhibitors Keywords: Neurofibromatosis Type1, NF1, Malignant Peripheral Nerve Sheath Tumor, MPNST, Neurofibrosarcomas, JQ1, BRD4 levels, BET inhibitor sensitivity and resistance, BET Bromodomain, PROTAC, ARV771 The authors have declared that no conflict of interest exists. Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 22, 2019; DOI: 10.1158/1078-0432.CCR-18-2437 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Cooper and Patel, et al. Page 2 Statement of Translational Relevance Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with no effective therapies. -
Download Product Insert (PDF)
PRODUCT INFORMATION BRD3 bromodomains 1 and 2 (human, recombinant) Item No. 14864 Overview and Properties Synonyms: Bromodomain containing protein 3, ORFX, RING3L, RING3-like protein Source: Recombinant N-terminal GST-tagged protein expressed in E. coli Amino Acids: 2-434 Uniprot No.: Q15059 Molecular Weight: 75.0 kDa Storage: -80°C (as supplied) Stability: ≥2 years Purity: batch specific (≥85% estimated by SDS-PAGE) Supplied in: 50 mM Tris, pH 8.0, with 150 mM sodium chloride and 20% glycerol Protein Concentration: batch specific mg/ml Activity: batch specific U/ml Specific Activity: batch specific U/mg Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Image 1 2 3 4 · · · · · · ·250 kDa · · · · · · ·150 kDa · · · · · · ·100 kDa · · · · · · ·75 kDa · · · · · · ·50 kDa · · · · · · ·37 kDa · · · · · · ·25 kDa · · · · · · ·20 kDa · · · · · · ·15 kDa Lane 1: BRD3 (4 µg) Lane 2: BRD3 (6 µg) Lane 3: BRD3 (8 µg) Lane 4: MW Markers WARNING CAYMAN CHEMICAL THIS PRODUCT IS FOR RESEARCH ONLY - NOT FOR HUMAN OR VETERINARY DIAGNOSTIC OR THERAPEUTIC USE. 1180 EAST ELLSWORTH RD SAFETY DATA ANN ARBOR, MI 48108 · USA This material should be considered hazardous until further information becomes available. Do not ingest, inhale, get in eyes, on skin, or on clothing. Wash thoroughly after handling. Before use, the user must review the complete Safety Data Sheet, which has been sent via email to your institution. PHONE: [800] 364-9897 WARRANTY AND LIMITATION OF REMEDY [734] 971-3335 Buyer agrees to purchase the material subject to Cayman’s Terms and Conditions. Complete Terms and Conditions including Warranty and Limitation of Liability information can be found on our website. -
Discovery of a Hidden Transient State in All Bromodomain Families
Discovery of a hidden transient state in all bromodomain families Lluís Raicha, Katharina Meierb, Judith Güntherc, Clara D. Christc, Frank Noéa,d,1, and Simon Olssona,1,2 aDepartment of Mathematics and Computer Science, Freie Universität Berlin, 14195 Berlin, Germany; bComputational Molecular Design, Pharmaceuticals, R&D, Bayer AG, 42096 Wuppertal, Germany; cComputational Molecular Design, Pharmaceuticals, R&D, Bayer AG, 13342 Berlin, Germany; and dDepartment of Chemistry, Rice University, Houston, TX 77005 Edited by David Baker, University of Washington, Seattle, WA, and approved December 1, 2020 (received for review August 17, 2020) Bromodomains (BDs) are small protein modules that interact with comprised by a four-helix bundle (αZ, αA, αB,andαC) with two acetylated marks in histones. These posttranslational modifica- principal loops that connect them (ZA- and BC-loops), con- tions are pivotal to regulate gene expression, making BDs prom- forming a hydrophobic pocket that is suited for acetyl-lysine ising targets to treat several diseases. While the general structure binding (Fig. 1) (24). The BC-loop contains a well-conserved hy- of BDs is well known, their dynamical features and their interplay drogen bond donor or “reader”—usually an asparagine—that is with other macromolecules are poorly understood, hampering the key for recognition. The ZA-loop is the longest loop and the one rational design of potent and selective inhibitors. Here, we com- that displays more variability in terms of sequence and structure, bine extensive molecular dynamics simulations, Markov state presenting short helices, turns, and even hairpin insertions in BD modeling, and available structural data to reveal a transiently family VIII (Fig. -
Targeting MYC Dependence in Cancer by Inhibiting BET Bromodomains
Targeting MYC dependence in cancer by inhibiting BET bromodomains Jennifer A. Mertz1, Andrew R. Conery1, Barbara M. Bryant, Peter Sandy, Srividya Balasubramanian, Deanna A. Mele, Louise Bergeron, and Robert J. Sims III2 Constellation Pharmaceuticals, Inc., Cambridge, MA 02142 Edited* by Robert N. Eisenman, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved August 30, 2011 (received for review May 23, 2011) The MYC transcription factor is a master regulator of diverse in preclinical animal models of endotoxic shock caused by acti- cellular functions and has been long considered a compelling vation of Toll-like receptors that trigger the up-regulation of therapeutic target because of its role in a range of human cytokines controlled by NF-κB (7). Importantly, although RNAi- malignancies. However, pharmacologic inhibition of MYC function mediated depletion of any one individual BET protein has broad has proven challenging because of both the diverse mechanisms effects on transcription, pharmacologic inhibition of the BET driving its aberrant expression and the challenge of disrupting bromodomains perturbs the transcription of a narrower range protein–DNA interactions. Here, we demonstrate the rapid and po- of genes (7). These findings suggest an opportunity to use BET- tent abrogation of MYC gene transcription by representative small bromodomain inhibitors to fine-tune key regulatory pathways for molecule inhibitors of the BET family of chromatin adaptors. MYC therapeutic benefit. transcriptional suppression was observed in the context of the nat- BET inhibitors exhibit anticancer effects in both in vitro and ural, chromosomally translocated, and amplified gene locus. Inhi- in vivo models of midline carcinoma (8), a rare but lethal disease bition of BET bromodomain–promoter interactions and subsequent that frequently harbors a chromosomal translocation in which reduction of MYC transcript and protein levels resulted in G1 arrest the bromodomains of BRD4 are fused to the NUT gene (9). -
Acetyltransferase Machinery Conserved in P300/CBP-Family Proteins
Oncogene (2002) 21, 2253 ± 2260 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc SHORT REPORT Acetyltransferase machinery conserved in p300/CBP-family proteins L Wuchao Yuan1 and Antonio Giordano*,2 1Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, MA 02118, USA; 2Department of Pathology, Anatomy and Cell Biology, Jeerson Medical College, Philadelphia, Pennsylvania, PA 19107, USA CREB-binding protein (CBP) and p300 are highly supports this proposal. Later, this protein family was conserved and functionally related transcription coacti- expanded after the discovery of Drosophila CBP (dCBP), vators and histone/protein acetyltransferases. They are which was also able to bind to E1A and coactivate tumor suppressors, participate in a wide variety of CREB-dependent transactivation (Akimaru et al., physiological events, and serve as integrators among 1997a). Recently, p300/CBP-like proteins of the plant dierent signal transduction pathways. In this study, 11 Arabidopsis thaliana have been reported (Bordoli et al., distinct proteins that have a high degree of homology 2001), suggesting that they are possible members of the with the amino acid sequence of p300 have been p300/CBP family. It is interesting to know how large the identi®ed in current protein databases. All of these 11 p300/CBP protein family could be and how this family of proteins belong to either animal or plant multicellular proteins is conserved evolutionarily. organisms (higher eucaryotes). Conservation of p300/ Taking advantage of recent progress in genomic CBP domains among these proteins was examined sequencing of dierent organisms, we performed a blast further by sequence alignment and pattern search. -
BET Family Members Bdf1/2 Modulate Global Transcription Initiation and Elongation in Saccharomyces Cerevisiae Rafal Donczew*, Steven Hahn*
RESEARCH ARTICLE BET family members Bdf1/2 modulate global transcription initiation and elongation in Saccharomyces cerevisiae Rafal Donczew*, Steven Hahn* Fred Hutchinson Cancer Research Center, Division of Basic Sciences, Seattle, United States Abstract Human bromodomain and extra-terminal domain (BET) family members are promising targets for therapy of cancer and immunoinflammatory diseases, but their mechanisms of action and functional redundancies are poorly understood. Bdf1/2, yeast homologues of the human BET factors, were previously proposed to target transcription factor TFIID to acetylated histone H4, analogous to bromodomains that are present within the largest subunit of metazoan TFIID. We investigated the genome-wide roles of Bdf1/2 and found that their important contributions to transcription extend beyond TFIID function as transcription of many genes is more sensitive to Bdf1/2 than to TFIID depletion. Bdf1/2 co-occupy the majority of yeast promoters and affect preinitiation complex formation through recruitment of TFIID, Mediator, and basal transcription factors to chromatin. Surprisingly, we discovered that hypersensitivity of genes to Bdf1/2 depletion results from combined defects in transcription initiation and early elongation, a striking functional similarity to human BET proteins, most notably Brd4. Our results establish Bdf1/2 as critical for yeast transcription and provide important mechanistic insights into the function of BET proteins in all eukaryotes. *For correspondence: [email protected] (RD); Introduction [email protected] (SH) Bromodomains (BDs) are reader modules that allow protein targeting to chromatin via interactions with acetylated histone tails. BD-containing factors are usually involved in gene transcription, and Competing interests: The their deregulation has been implicated in a spectrum of cancers and immunoinflammatory and neu- authors declare that no rological conditions (Fujisawa and Filippakopoulos, 2017; Wang et al., 2021).