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Super elongation complex

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https://www.readbyqxmd.com/read/28407486/transcriptional-elongation-of-hsv-immediate-early-genes-by-the-super-elongation-complex-drives-lytic-infection-and-reactivation-from-latency
#1
Roberto Alfonso-Dunn, Anne-Marie W Turner, Pierre M Jean Beltran, Jesse H Arbuckle, Hanna G Budayeva, Ileana M Cristea, Thomas M Kristie
The cellular transcriptional coactivator HCF-1 is required for initiation of herpes simplex virus (HSV) lytic infection and for reactivation from latency in sensory neurons. HCF-1 stabilizes the viral Immediate Early (IE) gene enhancer complex and mediates chromatin transitions to promote IE transcription initiation. In infected cells, HCF-1 was also found to be associated with a network of transcription elongation components including the super elongation complex (SEC). IE genes exhibit characteristics of genes controlled by transcriptional elongation, and the SEC-P-TEFb complex is specifically required to drive the levels of productive IE mRNAs...
April 12, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28350987/the-super-elongation-complex-drives-neural-stem-cell-fate-commitment
#2
Kun Liu, Dan Shen, Jingwen Shen, Shihong M Gao, Bo Li, Chouin Wong, Weidong Feng, Yan Song
Asymmetric stem cell division establishes an initial difference between a stem cell and its differentiating sibling, critical for maintaining homeostasis and preventing carcinogenesis. Yet the mechanisms that consolidate and lock in such initial fate bias remain obscure. Here, we use Drosophila neuroblasts to demonstrate that the super elongation complex (SEC) acts as an intrinsic amplifier to drive cell fate commitment. SEC is highly expressed in neuroblasts, where it promotes self-renewal by physically associating with Notch transcription activation complex and enhancing HES (hairy and E(spl)) transcription...
March 27, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28350981/asymmetric-notch-amplification-to-secure-stem-cell-identity
#3
Anthony M Rossi, Claude Desplan
Stem cells self-renew and produce progenitors with limited proliferative potential. Reporting in Developmental Cell, Liu et al. (2017) demonstrate that in some neural stem cells, Notch activity is asymmetrically amplified by a positive feedback loop with the super elongation complex (SEC) to quickly differentiate between stem cells and progenitors.
March 27, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28340332/super-elongation-complex-promotes-early-hiv-transcription-and-its-function-is-modulated-by-p-tefb
#4
Alona Kuzmina, Simona Krasnopolsky, Ran Taube
Early work on the control of transcription of the human immunodeficiency virus (HIV) laid the foundation for our current knowledge of how RNA Polymerase II is released from promoter-proximal pausing sites and transcription elongation is enhanced. The viral Tat activator recruits Positive Transcription Elongation Factor b (P-TEFb) and Super Elongation Complex (SEC) that jointly drive transcription elongation. While substantial progress in understanding the role of SEC in HIV gene transcription elongation has been obtained, defining of the mechanisms that govern SEC functions is still limited, and the role of SEC in controlling HIV transcription in the absence of Tat is less clear...
February 17, 2017: Transcription
https://www.readbyqxmd.com/read/28242784/mixed-lineage-leukemia-fusions-and-chromatin-in-leukemia
#5
Andrei V Krivtsov, Takayuki Hoshii, Scott A Armstrong
Recent studies have shown the importance of chromatin-modifying complexes in the maintenance of developmental gene expression and human disease. The mixed lineage leukemia gene (MLL1) encodes a chromatin-modifying protein and was discovered as a result of the cloning of translocations involved in human leukemias. MLL1 is a histone lysine 4 (H3K4) methyltransferase that supports transcription of genes that are important for normal development including homeotic (Hox) genes. MLL1 rearrangements result in expression of fusion proteins without H3K4 methylation activity but may gain the ability to recruit other chromatin-associated complexes such as the H3K79 methyltransferase DOT1L and the super elongation complex...
February 27, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28134250/structural-basis-for-ell2-and-aff4-activation-of-hiv-1-proviral-transcription
#6
Shiqian Qi, Zichong Li, Ursula Schulze-Gahmen, Goran Stjepanovic, Qiang Zhou, James H Hurley
The intrinsically disordered scaffold proteins AFF1/4 and the transcription elongation factors ELL1/2 are core components of the super elongation complex required for HIV-1 proviral transcription. Here we report the 2.0-Å resolution crystal structure of the human ELL2 C-terminal domain bound to its 50-residue binding site on AFF4, the ELLBow. The ELL2 domain has the same arch-shaped fold as the tight junction protein occludin. The ELLBow consists of an N-terminal helix followed by an extended hairpin that we refer to as the elbow joint, and occupies most of the concave surface of ELL2...
January 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28065413/therapeutic-targeting-of-mll-degradation-pathways-in-mll-rearranged-leukemia
#7
Kaiwei Liang, Andrew G Volk, Jeffrey S Haug, Stacy A Marshall, Ashley R Woodfin, Elizabeth T Bartom, Joshua M Gilmore, Laurence Florens, Michael P Washburn, Kelly D Sullivan, Joaquin M Espinosa, Joseph Cannova, Jiwang Zhang, Edwin R Smith, John D Crispino, Ali Shilatifard
Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex...
January 12, 2017: Cell
https://www.readbyqxmd.com/read/27984731/single-molecule-real-time-3d-imaging-of-the-transcription-cycle-by-modulation-interferometry
#8
Guanshi Wang, Jesse Hauver, Zachary Thomas, Seth A Darst, Alexandros Pertsinidis
Many essential cellular processes, such as gene control, employ elaborate mechanisms involving the coordination of large, multi-component molecular assemblies. Few structural biology tools presently have the combined spatial-temporal resolution and molecular specificity required to capture the movement, conformational changes, and subunit association-dissociation kinetics, three fundamental elements of how such intricate molecular machines work. Here, we report a 3D single-molecule super-resolution imaging study using modulation interferometry and phase-sensitive detection that achieves <2 nm axial localization precision, well below the few-nanometer-sized individual protein components...
December 15, 2016: Cell
https://www.readbyqxmd.com/read/27899651/a-permissive-chromatin-state-regulated-by-zfp281-aff3-in-controlling-the-imprinted-meg3-polycistron
#9
Yan Wang, Yang Shen, Qian Dai, Qian Yang, Yue Zhang, Xin Wang, Wei Xie, Zhuojuan Luo, Chengqi Lin
Genomic imprinting is an epigenetic regulation that leads to gene expression in a parent-of-origin specific manner. AFF3, the central component of the Super Elongation Complex-like 3 (SEC-L3), is enriched at both the intergenic-differentially methylated region (IG-DMR) and the Meg3 enhancer within the imprinted Dlk1-Dio3 locus to regulate the allele-specific gene expression in this locus. The localization of AFF3 to IG-DMR requires ZFP57. However, how AFF3 functions at the Meg3 enhancer in maintaining allele-specific gene expression remains unclear...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27679741/ddx6-transfers-p-tefb-kinase-to-the-af4-af4n-aff1-super-elongation-complex
#10
Fabian Mück, Silvia Bracharz, Rolf Marschalek
AF4/AFF1 and AF5/AFF4 are both backbones for the assembly of "super elongation complexes" (SECs) that exert 2 distinct functions after the recruitment of P-TEFb from the 7SK snRNP: (1) initiation and elongation of RNA polymerase II gene transcription, and (2) modification of transcribed gene regions by distinct histone methylation patterns. In this study we aimed to investigate one of the initial steps, namely how P-TEFb is transferred from 7SK snRNPs to the SECs. In particular, we were interested in the role of DDX6 that we have recently identified as part of the AF4 complex...
2016: American Journal of Blood Research
https://www.readbyqxmd.com/read/27558685/pseudouridylation-of-7sk-snrna-promotes-7sk-snrnp-formation-to-suppress-hiv-1-transcription-and-escape-from-latency
#11
Yang Zhao, John Karijolich, Britt Glaunsinger, Qiang Zhou
The 7SK snRNA sequesters P-TEFb, a general transcription elongation factor and human co-factor for HIV-1 Tat protein, into the catalytically inactive 7SK snRNP Little is known about how 7SK RNA is regulated to perform this function. Here, we show that most of 7SK is pseudouridylated at position U250 by the predominant cellular pseudouridine synthase machinery, the DKC1-box H/ACA RNP Pseudouridylation is critical to stabilize 7SK snRNP, as its abolishment by either mutation at or around U250 or depletion of DKC1, the catalytic component of the box H/ACA RNP, disrupts 7SK snRNP and releases P-TEFb to form the super elongation complex (SEC) and the Brd4-P-TEFb complex...
October 2016: EMBO Reports
https://www.readbyqxmd.com/read/27353326/multiple-p-tefbs-cooperatively-regulate-the-release-of-promoter-proximally-paused-rna-polymerase-ii
#12
Xiaodong Lu, Xinxing Zhu, You Li, Min Liu, Bin Yu, Yu Wang, Muhua Rao, Haiyang Yang, Kai Zhou, Yao Wang, Yanheng Chen, Meihua Chen, Songkuan Zhuang, Lin-Feng Chen, Runzhong Liu, Ruichuan Chen
The association of DSIF and NELF with initiated RNA Polymerase II (Pol II) is the general mechanism for inducing promoter-proximal pausing of Pol II. However, it remains largely unclear how the paused Pol II is released in response to stimulation. Here, we show that the release of the paused Pol II is cooperatively regulated by multiple P-TEFbs which are recruited by bromodomain-containing protein Brd4 and super elongation complex (SEC) via different recruitment mechanisms. Upon stimulation, Brd4 recruits P-TEFb to Spt5/DSIF via a recruitment pathway consisting of Med1, Med23 and Tat-SF1, whereas SEC recruits P-TEFb to NELF-A and NELF-E via Paf1c and Med26, respectively...
August 19, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27310306/collaboration-of-mllt1-enl-polycomb-and-atm-for-transcription-and-genome-integrity
#13
Ayako Ui, Akira Yasui
Polycomb group (PcG) repress, whereas Trithorax group (TrxG) activate transcription for tissue development and cellular proliferation, and misregulation of these factors is often associated with cancer. ENL (MLLT1) and AF9 (MLLT3) are fusion partners of Mixed Lineage Leukemia (MLL), TrxG proteins, and are factors in Super Elongation Complex (SEC). SEC controls transcriptional elongation to release RNA polymerase II, paused around transcription start site. In MLL rearranged leukemia, several components of SEC have been found as MLL-fusion partners and the control of transcriptional elongation is misregulated leading to tumorigenesis in MLL-SEC fused Leukemia...
April 25, 2016: Nucleus
https://www.readbyqxmd.com/read/27292648/t-bet-activates-th1-genes-through-mediator-and-the-super-elongation-complex
#14
Arnulf Hertweck, Catherine M Evans, Malihe Eskandarpour, Jonathan C H Lau, Kristine Oleinika, Ian Jackson, Audrey Kelly, John Ambrose, Peter Adamson, David J Cousins, Paul Lavender, Virginia L Calder, Graham M Lord, Richard G Jenner
The transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1 genes are occupied by H3K4me3 and RNA polymerase II in Th2 cells, while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and enhancers, where it activates enhancer RNA transcription...
June 21, 2016: Cell Reports
https://www.readbyqxmd.com/read/27223670/super-elongation-complex-contains-a-tfiif-related-subcomplex
#15
Bruce A Knutson, Marissa L Smith, Nancy Walker-Kopp, Xia Xu
Super elongation complex (SEC) belongs to a family of RNA polymerase II (Pol II) elongation factors that has similar properties as TFIIF, a general transcription factor that increases the transcription elongation rate by reducing pausing. Although SEC has TFIIF-like functional properties, it apparently lacks sequence and structural homology. Using HHpred, we find that SEC contains an evolutionarily related TFIIF-like subcomplex. We show that the SEC subunit ELL interacts with the Pol II Rbp2 subunit, as expected for a TFIIF-like factor...
August 7, 2016: Transcription
https://www.readbyqxmd.com/read/27063977/bromodomain-inhibitor-otx015-in-patients-with-acute-leukaemia-a-dose-escalation-phase-1-study
#16
Céline Berthon, Emmanuel Raffoux, Xavier Thomas, Norbert Vey, Carlos Gomez-Roca, Karen Yee, David Christopher Taussig, Keyvan Rezai, Christophe Roumier, Patrice Herait, Carmen Kahatt, Bruno Quesnel, Mauricette Michallet, Christian Recher, François Lokiec, Claude Preudhomme, Hervé Dombret
BACKGROUND: Bromodomain and extraterminal (BET) proteins are chromatin readers that preferentially affect the transcription of genes with super-enhancers, including oncogenes. BET proteins bind acetylated histone tails via their bromodomain, bringing the elongation complex to the promoter region. OTX015 (MK-8628) specifically binds to BRD2, BRD3, and BRD4, preventing BET proteins from binding to the chromatin, thus inhibiting gene transcription. OTX015 inhibits proliferation in many haematological malignancy cell lines and patient cells, in vitro and in vivo...
April 2016: Lancet Haematology
https://www.readbyqxmd.com/read/26830226/a-minor-subset-of-super-elongation-complexes-plays-a-predominant-role-in-reversing-hiv-1-latency
#17
Zichong Li, Huasong Lu, Qiang Zhou
Promoter-proximal pausing by RNA polymerase II (Pol II) is a key rate-limiting step in HIV-1 transcription and latency reversal. The viral Tat protein recruits human super elongation complexes (SECs) to paused Pol II to overcome this restriction. Despite the recent progress in understanding the functions of different subsets of SECs in controlling cellular and Tat-activated HIV transcription, little is known about the SEC subtypes that help reverse viral latency in CD4(+) T cells. Here, we used the CRISPR-Cas9 genome-editing tool to knock out the gene encoding the SEC subunit ELL2, AFF1, or AFF4 in Jurkat/2D10 cells, a well-characterized HIV-1 latency model...
April 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/26511279/meiotic-cohesin-based-chromosome-structure-is-essential-for-homologous-chromosome-pairing-in-schizosaccharomyces-pombe
#18
Da-Qiao Ding, Atsushi Matsuda, Kasumi Okamasa, Yuki Nagahama, Tokuko Haraguchi, Yasushi Hiraoka
Chromosome structure is dramatically altered upon entering meiosis to establish chromosomal architectures necessary for the successful progression of meiosis-specific events. An early meiotic event involves the replacement of the non-SMC mitotic cohesins with their meiotic equivalents in most part of the chromosome, forming an axis on meiotic chromosomes. We previously demonstrated that the meiotic cohesin complex is required for chromosome compaction during meiotic prophase in the fission yeast Schizosaccharomyces pombe...
June 2016: Chromosoma
https://www.readbyqxmd.com/read/26324710/calpain-cleaves-most-components-in-the-multiple-aminoacyl-trna-synthetase-complex-and-affects-their-functions
#19
Hui-Yan Lei, Xiao-Long Zhou, Zhi-Rong Ruan, Wei-Cheng Sun, Gilbert Eriani, En-Duo Wang
Nine aminoacyl-tRNA synthetases (aaRSs) and three scaffold proteins form a super multiple aminoacyl-tRNA synthetase complex (MSC) in the human cytoplasm. Domains that have been added progressively to MSC components during evolution are linked by unstructured flexible peptides, producing an elongated and multiarmed MSC structure that is easily attacked by proteases in vivo. A yeast two-hybrid screen for proteins interacting with LeuRS, a representative MSC member, identified calpain 2, a calcium-activated neutral cysteine protease...
October 23, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26279188/paf1-a-molecular-regulator-of-promoter-proximal-pausing-by-rna-polymerase-ii
#20
Fei Xavier Chen, Ashley R Woodfin, Alessandro Gardini, Ryan A Rickels, Stacy A Marshall, Edwin R Smith, Ramin Shiekhattar, Ali Shilatifard
The control of promoter-proximal pausing and the release of RNA polymerase II (Pol II) is a widely used mechanism for regulating gene expression in metazoans, especially for genes that respond to environmental and developmental cues. Here, we identify that Pol-II-associated factor 1 (PAF1) possesses an evolutionarily conserved function in metazoans in the regulation of promoter-proximal pausing. Reduction in PAF1 levels leads to an increased release of paused Pol II into gene bodies at thousands of genes. PAF1 depletion results in increased nascent and mature transcripts and increased levels of phosphorylation of Pol II's C-terminal domain on serine 2 (Ser2P)...
August 27, 2015: Cell
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