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https://www.readbyqxmd.com/read/28426192/profiling-cellular-substrates-of-lysine-acetyltransferases-gcn5-and-p300-with-orthogonal-labeling-and-click-chemistry
#1
Zhen Han, Chau-Wen Chou, Xiangkun Yang, Michael G Bartlett, Y George Zheng
p300 and GCN5 are two representative histone/lysine acetyltransferase (HAT/KAT) enzymes in mammalian cells. It was recently reported that they possess multiple acyltransferase activities including acetylation, propionylation, and butyrylation of the -amino group of lysine residues of histones and non-histone protein substrates. Although thousands of acetylated substrates and acetylation sites have been identified by mass spectrometry-based proteomic screening, our knowledge about protein acylation, especially the causative connection between individual KAT members and their substrates remain limited...
April 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28426094/sirt7-dependent-deacetylation-of-cdk9-activates-rna-polymerase-ii-transcription
#2
Maximilian F Blank, Sifan Chen, Fabian Poetz, Martina Schnölzer, Renate Voit, Ingrid Grummt
SIRT7 is an NAD+-dependent protein deacetylase that regulates cell growth and proliferation. Previous studies have shown that SIRT7 is required for RNA polymerase I (Pol I) transcription and pre-rRNA processing. Here, we took a proteomic approach to identify novel molecular targets and characterize the role of SIRT7 in non-nucleolar processes. We show that SIRT7 interacts with numerous proteins involved in transcriptional regulation and RNA metabolism, the majority of interactions requiring ongoing transcription...
March 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28424240/the-histone-acetyltransferase-gcn5-positively-regulates-t-cell-activation
#3
Beixue Gao, Qingfei Kong, Yana Zhang, Chawon Yun, Sharon Y R Dent, Jianxun Song, Donna D Zhang, Yiming Wang, Xuemei Li, Deyu Fang
Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of general control nonrepressed-protein 5 (Gcn5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. In this study, we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice, and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion, and differentiation...
April 19, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28412741/opposite-effects-of-gcn5-and-pcaf-knockdowns-on-the-alternative-mechanism-of-telomere-maintenance
#4
Maya Jeitany, Dalal Bakhos-Douaihy, David C Silvestre, Jose R Pineda, Nicolas Ugolin, Angela Moussa, Laurent R Gauthier, Didier Busso, Marie-Pierre Junier, Hervé Chneiweiss, Sylvie Chevillard, Chantal Desmaze, François D Boussin
Cancer cells can use a telomerase-independent mechanism, known as alternative lengthening of telomeres (ALT), to elongate their telomeres. General control non-derepressible 5 (GCN5) and P300/CBP-associated factor (PCAF) are two homologous acetyltransferases that are mutually exclusive subunits in SAGA-like complexes. Here, we reveal that down regulation of GCN5 and PCAF had differential effects on some phenotypic characteristics of ALT cells. Our results suggest that GCN5 is present at telomeres and opposes telomere recombination, in contrast to PCAF that may indirectly favour them in ALT cells...
February 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28412357/crystal-structure-of-pseudomonas-aeruginosa-n-acetyltransferase-pa4534
#5
Sungwook Shin, Jungwoo Choe
The GCN5-related N-acetyltransferase (GNAT) superfamily includes a large and diverse group of enzymes that catalyzes the transfer of an acetyl group from acetyl coenzyme A (Ac-CoA) to the amine group of a substrate. Substrates include protein N-terminus, lysine of histone tails, and other small molecules such as aminoglycoside, serotonin, and glucose-6-phosphate. GNAT superfamily of proteins is involved in many physiologically important reactions in eukaryotes and prokaryotes. However, functions of many GNATs remain unknown and PA4534 is one of those uncharacterized GNAT proteins from Pseudomonas aeruginosa...
April 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28401181/kat2-mediated-plk4-acetylation-contributes-to-genomic-stability-by-preserving-centrosome-number
#6
Marjorie Fournier, László Tora
We have recently identified the first human lysine (K) acetyltransferase 2A and 2B (called KAT2A/2B; known also as GCN5/PCAF, respectively)-dependent acetylome and revealed a mechanism by which KAT2A/2B-mediated acetylation of serine/threonine polo-like kinase 4 (PLK4) maintains correct centrosome number in human cells, therefore contributing to the maintenance of genome stability.(1).
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28400515/saga-complex-mediates-the-transcriptional-up-regulation-of-antiviral-rna-silencing
#7
Ida Bagus Andika, Atif Jamal, Hideki Kondo, Nobuhiro Suzuki
Pathogen recognition and transcriptional activation of defense-related genes are crucial steps in cellular defense responses. RNA silencing (RNAi) functions as an antiviral defense in eukaryotic organisms. Several RNAi-related genes are known to be transcriptionally up-regulated upon virus infection in some host organisms, but little is known about their induction mechanism. A phytopathogenic ascomycete, Cryphonectria parasitica (chestnut blight fungus), provides a particularly advantageous system to study RNAi activation, because its infection by certain RNA viruses induces the transcription of dicer-like 2 (dcl2) and argonaute-like 2 (agl2), two major RNAi players...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28334815/gcn5-mediated-rph1-acetylation-regulates-its-autophagic-degradation-under-dna-damage-stress
#8
Feng Li, Liang-De Zheng, Xin Chen, Xiaolu Zhao, Scott D Briggs, Hai-Ning Du
Histone modifiers regulate proper cellular activities in response to various environmental stress by modulating gene expression. In budding yeast, Rph1 transcriptionally represses many DNA damage or autophagy-related gene expression. However, little is known how Rph1 is regulated during these stress conditions. Here, we report that Rph1 is degraded upon DNA damage stress conditions. Notably, this degradation occurs via the autophagy pathway rather than through 26S proteasome proteolysis. Deletion of ATG genes or inhibition of vacuole protease activity compromises Rph1 turnover...
February 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28318979/a-phytophthora-effector-manipulates-host-histone-acetylation-and-reprograms-defense-gene-expression-to-promote-infection
#9
Liang Kong, Xufang Qiu, Jiangang Kang, Yang Wang, Han Chen, Jie Huang, Min Qiu, Yao Zhao, Guanghui Kong, Zhenchuan Ma, Yan Wang, Wenwu Ye, Suomeng Dong, Wenbo Ma, Yuanchao Wang
Immune response during pathogen infection requires extensive transcription reprogramming. A fundamental mechanism of transcriptional regulation is histone acetylation. However, how pathogens interfere with this process to promote disease remains largely unknown. Here we demonstrate that the cytoplasmic effector PsAvh23 produced by the soybean pathogen Phytophthora sojae acts as a modulator of histone acetyltransferase (HAT) in plants. PsAvh23 binds to the ADA2 subunit of the HAT complex SAGA and disrupts its assembly by interfering with the association of ADA2 with the catalytic subunit GCN5...
April 3, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28300060/h3-ubiquitination-by-nedd4-regulates-h3-acetylation-and-tumorigenesis
#10
Xian Zhang, Binkui Li, Abdol Hossein Rezaeian, Xiaohong Xu, Ping-Chieh Chou, Guoxiang Jin, Fei Han, Bo-Syong Pan, Chi-Yun Wang, Jie Long, Anmei Zhang, Chih-Yang Huang, Fuu-Jen Tsai, Chang-Hai Tsai, Christopher Logothetis, Hui-Kuan Lin
Dynamic changes in histone modifications under various physiological cues play important roles in gene transcription and cancer. Identification of new histone marks critical for cancer development is of particular importance. Here we show that, in a glucose-dependent manner, E3 ubiquitin ligase NEDD4 ubiquitinates histone H3 on lysine 23/36/37 residues, which specifically recruits histone acetyltransferase GCN5 for subsequent H3 acetylation. Genome-wide analysis of chromatin immunoprecipitation followed by sequencing reveals that NEDD4 regulates glucose-induced H3 K9 acetylation at transcription starting site and enhancer regions...
March 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28263968/snd1-acts-as-a-novel-gene-transcription-activator-recognizing-the-conserved-motif-domains-of-smad-promoters-inducing-tgf%C3%AE-1-response-and-breast-cancer-metastasis
#11
L Yu, Y Di, L Xin, Y Ren, X Liu, X Sun, W Zhang, Z Yao, J Yang
As an AEG-1/MTDH/LYRIC-binding protein, Staphylococcal nuclease domain-containing 1 (SND1) is upregulated in numerous human cancers where it has been assigned multiple functional roles. In this study, we discovered that SND1 was upregulated in breast cancer tissues, particularly the tissues from patients with distant metastases. The underlying molecular mechanisms demonstrated a novel role of SND1 in regulating the activity of transforming growth factor β1 (TGFβ1) signaling pathway, which promotes metastasis in breast cancer...
March 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28236225/backbone-resonance-assignment-of-an-insect-arylalkylamine-n-acetyltransferase-from-bombyx-mori-reveals-conformational-heterogeneity
#12
Adam A Aboalroub, Ziming Zhang, Dimitra Keramisanou, Ioannis Gelis
Arylalkylamine N-acetyltransferases (AANATs) catalyze the transfer of an acetyl group from the acetyl-group donor, acetyl-CoA, to an arylalkylamine acceptor. Although a single AANAT has been identified in mammals, insects utilize multiple AANATs in a diverse array of biological processes. AANATs belong to the GCN5-related acetyltransferase (GNAT) superfamily of enzymes, which despite their overall very low sequence homology, are characterized by a well conserved catalytic core domain. The structural properties of many GNATs have been extensively studied by X-ray crystallography that revealed common features during the catalytic cycle...
February 24, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28223282/induction-of-nkg2d-ligands-on-solid-tumors-requires-tumor-specific-cd8-t-cells-and-histone-acetyltransferases
#13
Jiemiao Hu, Chantale Bernatchez, Liangfang Zhang, Xueqing Xia, Eugenie S Kleinerman, Mien-Chie Hung, Patrick Hwu, Shulin Li
NKG2D-mediated immune surveillance is crucial for inhibiting tumor growth and metastases. Malignant tumor cells often downregulate NKG2D ligands to escape from immune surveillance. High-profile studies have shown that restoring NKG2D ligand expression via genetic engineering inhibits tumor formation and progression. However, no effective in vivo approaches are available to restore these ligands across different types of solid tumors because the classic stress signal-dependent induction of this ligand in vitro is transient and has rarely been duplicated in solid tumors in vivo We found that coadministration of an immune stimulatory signal (IL12) and chemotherapy (doxorubicin) restored the NKG2D ligand Rae-1 in multiple tumor types, including a human tumor model...
April 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28188175/gcn5-determines-the-fate-of-drosophila-germline-stem-cells-through-degradation-of-cyclin-a
#14
Tianqi Liu, Qi Wang, Wenqing Li, Feiyu Mao, Shanshan Yue, Sun Liu, Xiaona Liu, Shan Xiao, Laixin Xia
The fluctuating CDK-CYCLIN complex plays a general role in cell-cycle control. Many types of stem cells use unique features of the cell cycle to facilitate asymmetric division. However, the manner in which these features are established remains poorly understood. The cell cycle of Drosophila female germline stem cells (GSCs) is characterized by short G1 and very long G2 phases, making it an excellent model for the study of cell cycle control in stem cell fate determination. Using a Drosophila female GSCs model, we found Gcn5, the first discovered histone acetyltransferase, to maintain germline stem cells in Drosophila ovaries...
February 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28154153/diencephalic-size-is-restricted-by-a-novel-interplay-between-gcn5-acetyltransferase-activity-and-retinoic-acid-signaling
#15
Jonathan J Wilde, Julie A Siegenthaler, Sharon Y R Dent, Lee A Niswander
Diencephalic defects underlie an array of neurological diseases. Previous studies have suggested that retinoic acid (RA) signaling is involved in diencephalic development at late stages of embryonic development, but its roles and mechanisms of action during early neural development are still unclear. Here we demonstrate that mice lacking enzymatic activity of the acetyltransferase GCN5 ((Gcn5(hat/hat) )), which were previously characterized with respect to their exencephalic phenotype, exhibit significant diencephalic expansion, decreased diencephalic RA signaling, and increased diencephalic WNT and SHH signaling...
March 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28125090/loss-of-gcn5-leads-to-increased-neuronal-apoptosis-by-upregulating-e2f1-and-egr-1-dependent-bh3-only-protein-bim
#16
Yanna Wu, Shanshan Ma, Yong Xia, Yangpeng Lu, Shiyin Xiao, Yali Cao, Sidian Zhuang, Xiangpeng Tan, Qiang Fu, Longchang Xie, Zhiming Li, Zhongmin Yuan
Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons...
January 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28115623/sas3-and-ada2-gcn5-dependent-histone-h3-acetylation-is-required-for-transcription-elongation-at-the-de-repressed-flo1-gene
#17
Michael Church, Kim C Smith, Mohamed M Alhussain, Sari Pennings, Alastair B Fleming
The Saccharomyces cerevisiae FLO1 gene encodes a cell wall protein that imparts cell-cell adhesion. FLO1 transcription is regulated via the antagonistic activities of the Tup1-Cyc8 co-repressor and Swi-Snf co-activator complexes. Tup1-Cyc8 represses transcription through the organization of strongly positioned, hypoacetylated nucleosomes across gene promoters. Swi-Snf catalyzes remodeling of these nucleosomes in a mechanism involving histone acetylation that is poorly understood. Here, we show that FLO1 de-repression is accompanied by Swi-Snf recruitment, promoter histone eviction and Sas3 and Ada2(Gcn5)-dependent histone H3K14 acetylation...
January 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28002667/discovery-of-a-potent-cell-penetrant-and-selective-p300-cbp-associated-factor-pcaf-general-control-nonderepressible-5-gcn5-bromodomain-chemical-probe
#18
Philip G Humphreys, Paul Bamborough, Chun-Wa Chung, Peter D Craggs, Laurie Gordon, Paola Grandi, Thomas G Hayhow, Jameed Hussain, Katherine L Jones, Matthew Lindon, Anne-Marie Michon, Jessica F Renaux, Colin J Suckling, David F Tough, Rab K Prinjha
p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families...
January 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27993678/chemical-inhibition-of-the-histone-acetyltransferase-activity-in-arabidopsis-thaliana
#19
Felipe Aquea, Tania Timmermann, Ariel Herrera-Vásquez
Chemical inhibition of chromatin regulators provides an effective approach to investigate the roles of chromatin modifications in plant and animals. In this work, chemical inhibition of the Arabidopsis histone acetyltransferase activity by γ-butyrolactone (MB-3), the inhibitor of the catalytic activity of mammalian GENERAL CONTROL NON-REPRESSIBLE 5 (GCN5) is evaluated. Arabidopsis seedlings were germinated in LS medium supplemented with different concentrations of MB-3, and inhibition in the root length and yellowed leaves were observed...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27989438/chromatin-controls-dna-replication-origin-selection-lagging-strand-synthesis-and-replication-fork-rates
#20
Christoph F Kurat, Joseph T P Yeeles, Harshil Patel, Anne Early, John F X Diffley
The integrity of eukaryotic genomes requires rapid and regulated chromatin replication. How this is accomplished is still poorly understood. Using purified yeast replication proteins and fully chromatinized templates, we have reconstituted this process in vitro. We show that chromatin enforces DNA replication origin specificity by preventing non-specific MCM helicase loading. Helicase activation occurs efficiently in the context of chromatin, but subsequent replisome progression requires the histone chaperone FACT (facilitates chromatin transcription)...
January 5, 2017: Molecular Cell
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