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https://www.readbyqxmd.com/read/27731797/insights-into-hiv-1-proviral-transcription-from-integrative-structure-and-dynamics-of-the-tat-aff4-p-tefb-tar-complex
#1
Ursula Schulze-Gahmen, Ignacia Echeverria, Goran Stjepanovic, Yun Bai, Huasong Lu, Dina Schneidman-Duhovny, Jennifer A Doudna, Qiang Zhou, Andrej Sali, James H Hurley
HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 Å structure of HIV-1 TAR in complex with HIV-1 Tat and human AFF4, CDK9, and CycT1. The TAR central loop contacts the CycT1 Tat-TAR recognition motif (TRM) and the second Tat Zn(2+)-binding loop. Hydrogen-deuterium exchange (HDX) shows that AFF4 helix 2 is stabilized in the TAR complex despite not touching the RNA, explaining how it enhances TAR binding to the SEC 50-fold. RNA SHAPE and SAXS data were used to help model the extended (Tat Arginine-Rich Motif) ARM, which enters the TAR major groove between the bulge and the central loop...
October 12, 2016: ELife
https://www.readbyqxmd.com/read/27679741/ddx6-transfers-p-tefb-kinase-to-the-af4-af4n-aff1-super-elongation-complex
#2
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/26830226/a-minor-subset-of-super-elongation-complexes-plays-a-predominant-role-in-reversing-hiv-1-latency
#3
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/26171280/af4-and-af4n-protein-complexes-recruitment-of-p-tefb-kinase-their-interactome-and-potential-functions
#4
Bastian Scholz, Eric Kowarz, Tanja Rössler, Khalil Ahmad, Dieter Steinhilber, Rolf Marschalek
AF4/AFF1 and AF5/AFF4 are the molecular backbone to assemble "super-elongation complexes" (SECs) that have two main functions: (1) control of transcriptional elongation by recruiting the positive transcription elongation factor b (P-TEFb = CyclinT1/CDK9) that is usually stored in inhibitory 7SK RNPs; (2) binding of different histone methyltransferases, like DOT1L, NSD1 and CARM1. This way, transcribed genes obtain specific histone signatures (e.g. H3K79me2/3, H3K36me2) to generate a transcriptional memory system...
2015: American Journal of Blood Research
https://www.readbyqxmd.com/read/26007649/gene-target-specificity-of-the-super-elongation-complex-sec-family-how-hiv-1-tat-employs-selected-sec-members-to-activate-viral-transcription
#5
Huasong Lu, Zichong Li, Wei Zhang, Ursula Schulze-Gahmen, Yuhua Xue, Qiang Zhou
The AF4/FMR2 proteins AFF1 and AFF4 act as a scaffold to assemble the Super Elongation Complex (SEC) that strongly activates transcriptional elongation of HIV-1 and cellular genes. Although they can dimerize, it is unclear whether the dimers exist and function within a SEC in vivo. Furthermore, it is unknown whether AFF1 and AFF4 function similarly in mediating SEC-dependent activation of diverse genes. Providing answers to these questions, our current study shows that AFF1 and AFF4 reside in separate SECs that display largely distinct gene target specificities...
July 13, 2015: Nucleic Acids Research
https://www.readbyqxmd.com/read/25806092/methylation-analysis-of-histone-h4k12ac-associated-promoters-in-sperm-of-healthy-donors-and-subfertile-patients
#6
Markus Vieweg, Katerina Dvorakova-Hortova, Barbora Dudkova, Przemyslaw Waliszewski, Marie Otte, Berthold Oels, Amir Hajimohammad, Heiko Turley, Martin Schorsch, Hans-Christian Schuppe, Wolfgang Weidner, Klaus Steger, Agnieszka Paradowska-Dogan
BACKGROUND: Histone to protamine exchange and the hyperacetylation of the remaining histones are hallmarks of spermiogenesis. Acetylation of histone H4 at lysine 12 (H4K12ac) was observed prior to full decondensation of sperm chromatin after fertilization suggesting an important role for the regulation of gene expression in early embryogenesis. Similarly, DNA methylation may contribute to gene silencing of several developmentally important genes. Following the identification of H4K12ac-binding promoters in sperm of fertile and subfertile patients, we aimed to investigate whether the depletion of histone-binding is associated with aberrant DNA methylation in sperm of subfertile men...
2015: Clinical Epigenetics
https://www.readbyqxmd.com/read/25730767/germline-gain-of-function-mutations-in-aff4-cause-a-developmental-syndrome-functionally-linking-the-super-elongation-complex-and-cohesin
#7
Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, Ian D Krantz
Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia)...
April 2015: Nature Genetics
https://www.readbyqxmd.com/read/25319827/a-gene-specific-role-for-the-ssu72-rnapii-ctd-phosphatase-in-hiv-1-tat-transactivation
#8
Yupeng Chen, Lirong Zhang, Conchi Estarás, Seung H Choi, Luis Moreno, Jonathan Karn, James J Moresco, John R Yates, Katherine A Jones
HIV-1 Tat stimulates transcription elongation by recruiting the P-TEFb (positive transcription elongation factor-b) (CycT1:CDK9) C-terminal domain (CTD) kinase to the HIV-1 promoter. Here we show that Tat transactivation also requires the Ssu72 CTD Ser5P (S5P)-specific phosphatase, which mediates transcription termination and intragenic looping at eukaryotic genes. Importantly, HIV-1 Tat interacts directly with Ssu72 and strongly stimulates its CTD phosphatase activity. We found that Ssu72 is essential for Tat:P-TEFb-mediated phosphorylation of the S5P-CTD in vitro...
October 15, 2014: Genes & Development
https://www.readbyqxmd.com/read/24985467/a-single-point-mutation-in-cyclin-t1-eliminates-binding-to-hexim1-cdk9-and-rna-but-not-to-aff4-and-enforces-repression-of-hiv-transcription
#9
Alona Kuzmina, Nina Verstraete, Sigal Galker, Maayan Maatook, Olivier Bensaude, Ran Taube
BACKGROUND: Human immunodeficiency virus (HIV) gene expression is primarily regulated at the step of transcription elongation. The viral Tat protein recruits the Positive Transcription Elongation Factor b (P-TEFb) and the Super Elongation Complex (SEC) to the HIV promoter and enhances transcription by host RNA polymerase II. RESULTS: To map residues in the cyclin box of cyclin T1 that mediate the binding of P-TEFb to its interacting host partners and support HIV transcription, a pool of N-terminal cyclin T1 mutants was generated...
July 1, 2014: Retrovirology
https://www.readbyqxmd.com/read/24843025/aff4-binding-to-tat-p-tefb-indirectly-stimulates-tar-recognition-of-super-elongation-complexes-at-the-hiv-promoter
#10
Ursula Schulze-Gahmen, Huasong Lu, Qiang Zhou, Tom Alber
Superelongation complexes (SECs) are essential for transcription elongation of many human genes, including the integrated HIV-1 genome. At the HIV-1 promoter, the viral Tat protein binds simultaneously to the nascent TAR RNA and the CycT1 subunit of the P-TEFb kinase in a SEC. To understand the preferential recruitment of SECs by Tat and TAR, we determined the crystal structure of a quaternary complex containing Tat, P-TEFb, and the SEC scaffold, AFF4. Tat and AFF4 fold on the surface of CycT1 and interact directly...
April 24, 2014: ELife
https://www.readbyqxmd.com/read/24727379/crystal-structure-of-hiv-1-tat-complexed-with-human-p-tefb-and-aff4
#11
Jianyou Gu, Nigar D Babayeva, Yoshiaki Suwa, Andrey G Baranovskiy, David H Price, Tahir H Tahirov
Developing anti-viral therapies targeting HIV-1 transcription has been hampered by the limited structural knowledge of the proteins involved. HIV-1 hijacks the cellular machinery that controls RNA polymerase II elongation through an interaction of HIV-1 Tat with the positive transcription elongation factor P-TEFb, which interacts with an AF4 family member (AFF1/2/3/4) in the super elongation complex (SEC). Because inclusion of Tat•P-TEFb into the SEC is critical for HIV transcription, we have determined the crystal structure of the Tat•AFF4•P-TEFb complex containing HIV-1 Tat (residues 1-48), human Cyclin T1 (1-266), human Cdk9 (7-332), and human AFF4 (27-69)...
2014: Cell Cycle
https://www.readbyqxmd.com/read/24515107/release-of-positive-transcription-elongation-factor-b-p-tefb-from-7sk-small-nuclear-ribonucleoprotein-snrnp-activates-hexamethylene-bisacetamide-inducible-protein-hexim1-transcription
#12
Pingyang Liu, Yanhui Xiang, Koh Fujinaga, Koen Bartholomeeusen, Kyle A Nilson, David H Price, B Matija Peterlin
By phosphorylating negative elongation factors and the C-terminal domain of RNA polymerase II (RNAPII), positive transcription elongation factor b (P-TEFb), which is composed of CycT1 or CycT2 and CDK9, activates eukaryotic transcription elongation. In growing cells, it is found in active and inactive forms. In the former, free P-TEFb is a potent transcriptional coactivator. In the latter, it is inhibited by HEXIM1 or HEXIM2 in the 7SK small nuclear ribonucleoprotein (snRNP), which contains, additionally, 7SK snRNA, methyl phosphate-capping enzyme (MePCE), and La-related protein 7 (LARP7)...
April 4, 2014: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/23746844/hif1a-employs-cdk8-mediator-to-stimulate-rnapii-elongation-in-response-to-hypoxia
#13
Matthew D Galbraith, Mary A Allen, Claire L Bensard, Xiaoxing Wang, Marie K Schwinn, Bo Qin, Henry W Long, Danette L Daniels, William C Hahn, Robin D Dowell, Joaquín M Espinosa
The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates RNA polymerase II (RNAPII). We report here that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation. The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. HIF1A induces binding of CDK8-Mediator and the super elongation complex (SEC), containing AFF4 and CDK9, to alleviate RNAPII pausing...
June 6, 2013: Cell
https://www.readbyqxmd.com/read/23471103/the-aff4-scaffold-binds-human-p-tefb-adjacent-to-hiv-tat
#14
Ursula Schulze-Gahmen, Heather Upton, Andrew Birnberg, Katherine Bao, Seemay Chou, Nevan J Krogan, Qiang Zhou, Tom Alber
Human positive transcription elongation factor b (P-TEFb) phosphorylates RNA polymerase II and regulatory proteins to trigger elongation of many gene transcripts. The HIV-1 Tat protein selectively recruits P-TEFb as part of a super elongation complex (SEC) organized on a flexible AFF1 or AFF4 scaffold. To understand this specificity and determine if scaffold binding alters P-TEFb conformation, we determined the structure of a tripartite complex containing the recognition regions of P-TEFb and AFF4. AFF4 meanders over the surface of the P-TEFb cyclin T1 (CycT1) subunit but makes no stable contacts with the CDK9 kinase subunit...
March 5, 2013: ELife
https://www.readbyqxmd.com/read/23251033/hiv-1-tat-recruits-transcription-elongation-factors-dispersed-along-a-flexible-aff4-scaffold
#15
Seemay Chou, Heather Upton, Katherine Bao, Ursula Schulze-Gahmen, Avi J Samelson, Nanhai He, Anna Nowak, Huasong Lu, Nevan J Krogan, Qiang Zhou, Tom Alber
The HIV-1 Tat protein stimulates viral gene expression by recruiting human transcription elongation complexes containing P-TEFb, AFF4, ELL2, and ENL or AF9 to the viral promoter, but the molecular organization of these complexes remains unknown. To establish the overall architecture of the HIV-1 Tat elongation complex, we mapped the binding sites that mediate complex assembly in vitro and in vivo. The AFF4 protein emerges as the central scaffold that recruits other factors through direct interactions with short hydrophobic regions along its structurally disordered axis...
January 8, 2013: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/23050902/ribavirin-induced-intracellular-gtp-depletion-activates-transcription-elongation-in-coagulation-factor-vii-gene-expression
#16
Atsuo Suzuki, Yuhri Miyawaki, Eriko Okuyama, Moe Murata, Yumi Ando, Io Kato, Yuki Takagi, Akira Takagi, Takashi Murate, Hidehiko Saito, Tetsuhito Kojima
Coagulation FVII (Factor VII) is a vitamin K-dependent glycoprotein synthesized in hepatocytes. It was reported previously that FVII gene (F7) expression was up-regulated by ribavirin treatment in hepatitis C virus-infected haemophilia patients; however, its precise mechanism is still unknown. In the present study, we investigated the molecular mechanism of ribavirin-induced up-regulation of F7 expression in HepG2 (human hepatoma cell line). We found that intracellular GTP depletion by ribavirin as well as other IMPDH (inosine-5'-monophosphate dehydrogenase) inhibitors, such as mycophenolic acid and 6-mercaptopurine, up-regulated F7 expression...
January 1, 2013: Biochemical Journal
https://www.readbyqxmd.com/read/22547686/the-super-elongation-complex-family-of-rna-polymerase-ii-elongation-factors-gene-target-specificity-and-transcriptional-output
#17
Zhuojuan Luo, Chengqi Lin, Erin Guest, Alexander S Garrett, Nima Mohaghegh, Selene Swanson, Stacy Marshall, Laurence Florens, Michael P Washburn, Ali Shilatifard
The elongation stage of transcription is highly regulated in metazoans. We previously purified the AFF1- and AFF4-containing super elongation complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL/MLLT1, and AF9/MLLT3. The SEC family members demonstrate high levels of polymerase II (Pol II) C-terminal domain kinase activity; however, only SEC is required for the proper induction of the HSP70 gene upon stress...
July 2012: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/22528490/regulation-of-amp-activated-protein-kinase-signaling-by-aff4-protein-member-of-af4-all1-fused-gene-from-chromosome-4-family-of-transcription-factors-in-hypothalamic-neurons
#18
Tadasuke Komori, Asako Doi, Tetsuya Nosaka, Hiroto Furuta, Takashi Akamizu, Toshio Kitamura, Emiko Senba, Yoshihiro Morikawa
In the hypothalamus, fasting induces a member of the AF4 family of transcription factors, AFF4, which was originally identified as a fusion partner of the mixed-lineage leukemia gene in infant acute lymphoblastic leukemia. However, the roles of AFF4 in the hypothalamus remain unclear. We show herein that expression of AFF4 increased upon addition of ghrelin and fasting in the growth hormone secretagogue receptor-expressing neurons of the hypothalamus. In the growth hormone secretagogue receptor-expressing hypothalamic neuronal cell line GT1-7, ghrelin markedly induced expression of AFF4 in a time- and dose-dependent manner...
June 8, 2012: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/22483617/the-ubiquitin-ligase-siah1-controls-ell2-stability-and-formation-of-super-elongation-complexes-to-modulate-gene-transcription
#19
Min Liu, Joanne Hsu, Caleb Chan, Zichong Li, Qiang Zhou
Super elongation complexes (SECs) contain two different transcription elongation factors, P-TEFb and ELL1/2, linked by the scaffolding protein AFF4 or AFF1. They stimulate the expression of both normal and disease-related genes, especially those of HIV or those involved in leukemogenesis. Among all SEC subunits, ELL2 is stoichiometrically limiting and uniquely regulated at the level of protein stability. Here we identify the RING domain protein Siah1, but not the homologous Siah2, as the E3 ubiquitin ligase for ELL2 polyubiquitination and proteasomal degradation...
May 11, 2012: Molecular Cell
https://www.readbyqxmd.com/read/22252557/ell-facilitates-rna-polymerase-ii-pause-site-entry-and-release
#20
Jung S Byun, Temesgen D Fufa, Clay Wakano, Alfonso Fernandez, Cynthia M Haggerty, Myong-Hee Sung, Kevin Gardner
Transcription is a multi-stage process that coordinates several steps within the transcription cycle including chromatin reorganization, RNA polymerase II recruitment, initiation, promoter clearance and elongation. Recent advances have identified the super elongation complex, containing the eleven-nineteen lysine-rich leukaemia (ELL) protein, as a key regulator of transcriptional elongation. Here we show that ELL has a diverse and kinetically distinct role before its assembly into the super elongation complex by stabilizing Pol II recruitment/initiation and entry into the pause site...
2012: Nature Communications
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