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https://www.readbyqxmd.com/read/28188175/gcn5-determines-the-fate-of-drosophila-germline-stem-cells-through-degradation-of-cyclin-a
#1
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
#2
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...
February 2, 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
#3
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
#4
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
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/27966810/discovery-of-a-pcaf-bromodomain-chemical-probe
#8
Moses Moustakim, Peter G K Clark, Laura Trulli, Angel L Fuentes de Arriba, Matthias T Ehebauer, Apirat Chaikuad, Emma J Murphy, Jacqui Mendez-Johnson, Danette Daniels, Chun-Feng D Hou, Yu-Hui Lin, John R Walker, Raymond Hui, Hongbing Yang, Lucy Dorrell, Catherine M Rogers, Octovia P Monteiro, Oleg Fedorov, Kilian V M Huber, Stefan Knapp, Jag Heer, Darren J Dixon, Paul E Brennan
The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3...
December 14, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27942754/a-copper-responsive-promoter-replacement-system-to-investigate-gene-functions-in-trichoderma-reesei-a-case-study-in-characterizing-saga-genes
#9
Fanglin Zheng, Yanli Cao, Xinxing Lv, Lei Wang, Chunyan Li, Weixin Zhang, Guanjun Chen, Weifeng Liu
Trichoderma reesei represents an important workhorse for industrial production of cellulases as well as other proteins. The molecular mechanism underlying the regulation of cellulase production as well as other physiological processes in T. reesei is still insufficiently understood. We constructed a P tcu1 -based promoter substitution cassette that allowed one-step replacement of the endogenous promoter for controlling the target gene expression with copper. We then showed that copper repression of the histone acetyltransferase gene gcn5 phenocopied the gcn5 deletion strain...
December 9, 2016: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27922451/direct-screening-for-chromatin-status-on-dna-barcodes-in-yeast-delineates-the-regulome-of-h3k79-methylation-by-dot1
#10
Hanneke Vlaming, Thom M Molenaar, Tibor van Welsem, Deepani W Poramba-Liyanage, Desiree E Smith, Arno Velds, Liesbeth Hoekman, Tessy Korthout, Sjoerd Hendriks, A F Maarten Altelaar, Fred van Leeuwen
Given the frequent misregulation of chromatin in cancer, it is important to understand the cellular mechanisms that regulate chromatin structure. However, systematic screening for epigenetic regulators is challenging and often relies on laborious assays or indirect reporter read-outs. Here we describe a strategy, Epi-ID, to directly assess chromatin status in thousands of mutants. In Epi-ID, chromatin status on DNA barcodes is interrogated by chromatin immunoprecipitation followed by deep sequencing, allowing for quantitative comparison of many mutants in parallel...
6, 2016: ELife
https://www.readbyqxmd.com/read/27903907/chromatin-binding-of-gcn5-in-drosophila-is-largely-mediated-by-cp190
#11
Tamer Ali, Marcus Krüger, Sabin Bhuju, Michael Jarek, Marek Bartkuhn, Rainer Renkawitz
Centrosomal 190 kDa protein (CP190) is a promoter binding factor, mediates long-range interactions in the context of enhancer-promoter contacts and in chromosomal domain formation. All Drosophila insulator proteins bind CP190 suggesting a crucial role in insulator function. CP190 has major effects on chromatin, such as depletion of nucleosomes, high nucleosomal turnover and prevention of heterochromatin expansion. Here, we searched for enzymes, which might be involved in CP190 mediated chromatin changes. Eighty percent of the genomic binding sites of the histone acetyltransferase Gcn5 are colocalizing with CP190 binding...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27899560/not5-dependent-co-translational-assembly-of-ada2-and-spt20-is-essential-for-functional-integrity-of-saga
#12
Sari Kassem, Zoltan Villanyi, Martine A Collart
Acetylation of histones regulates gene expression in eukaryotes. In the yeast Saccharomyces cerevisiae it depends mainly upon the ADA and SAGA histone acetyltransferase complexes for which Gcn5 is the catalytic subunit. Previous screens have determined that global acetylation is reduced in cells lacking subunits of the Ccr4-Not complex, a global regulator of eukaryotic gene expression. In this study we have characterized the functional connection between the Ccr4-Not complex and SAGA. We show that SAGA mRNAs encoding a core set of SAGA subunits are tethered together for co-translational assembly of the encoded proteins...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27894818/supt20-is-required-for-development-of-the-axial-skeleton
#13
Sunita Warrier, Samer Nuwayhid, Julia A Sabatino, Kelsey F Sugrue, Irene E Zohn
Somitogenesis and subsequent axial skeletal development is regulated by the interaction of pathways that determine the periodicity of somite formation, rostrocaudal somite polarity and segment identity. Here we use a hypomorphic mutant mouse line to demonstrate that Supt20 (Suppressor of Ty20) is required for development of the axial skeleton. Supt20 hypomorphs display fusions of the ribs and vertebrae at lower thoracic levels along with anterior homeotic transformation of L1 to T14. These defects are preceded by reduction of the rostral somite and posterior shifts in Hox gene expression...
January 15, 2017: Developmental Biology
https://www.readbyqxmd.com/read/27876471/cobalamin-and-folate-protect-mitochondrial-and-contractile-functions-in-a-murine-model-of-cardiac-pressure-overload
#14
Jérôme Piquereau, Maryline Moulin, Giada Zurlo, Philippe Mateo, Mélanie Gressette, Jean-Louis Paul, Christophe Lemaire, Renée Ventura-Clapier, Vladimir Veksler, Anne Garnier
PGC-1α, a key regulator of energy metabolism, seems to be a relevant therapeutic target to rectify the energy deficit observed in heart failure (HF). Since our previous work has shown positive effects of cobalamin (Cb) on PGC-1α cascade, we investigate the protective role of Cb in pressure overload-induced myocardial dysfunction. Mice were fed with normal diet (ND) or with Cb and folate supplemented diet (SD) 3weeks before and 4weeks after transverse aortic constriction (TAC). At the end, left ventricle hypertrophy and drop of ejection fraction were significantly lower in SD mice than in ND mice...
November 20, 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/27874008/the-gcn5-cited2-pka-signalling-module-controls-hepatic-glucose-metabolism-through-a-camp-induced-substrate-switch
#15
Mashito Sakai, Tomoko Tujimura-Hayakawa, Takashi Yagi, Hiroyuki Yano, Masaru Mitsushima, Hiroyuki Unoki-Kubota, Yasushi Kaburagi, Hiroshi Inoue, Yoshiaki Kido, Masato Kasuga, Michihiro Matsumoto
Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon-cAMP-protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1α to inhibit gluconeogenesis in the fed state...
November 22, 2016: Nature Communications
https://www.readbyqxmd.com/read/27816487/arylalkylamine-n-acetyltransferase-1-gene-tcaanat1-is-required-for-cuticle-morphology-and-pigmentation-of-the-adult-red-flour-beetle-tribolium-castaneum
#16
Mi Young Noh, Bonwoo Koo, Karl J Kramer, Subbaratnam Muthukrishnan, Yasuyuki Arakane
In the insect cuticle tanning pathway (sclerotization and pigmentation), the enzyme arylalkylamine N-acetyltransferase (AANAT) catalyzes the acetylation of dopamine to form N-acetyldopamine (NADA), which is one of the major precursors for quinone-mediated tanning. In this study we characterized and investigated the function of TcAANAT1 in cuticle pigmentation of the red flour beetle, Tribolium castaneum. We isolated a full length TcAANAT1 cDNA that encodes a protein of 256 amino acid residues with a predicted GCN5-related acetyltransferase domain containing an acetyl-CoA binding motif...
November 2, 2016: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27803161/molecular-basis-for-cohesin-acetylation-by-establishment-of-sister-chromatid-cohesion-n-acetyltransferase-esco1
#17
Yadilette Rivera-Colón, Andrew Maguire, Glen P Liszczak, Adam S Olia, Ronen Marmorstein
Protein acetylation is a prevalent posttranslational modification that is regulated by diverse acetyltransferase enzymes. Although histone acetyltransferases (HATs) have been well characterized both structurally and mechanistically, far less is known about non-histone acetyltransferase enzymes. The human ESCO1 and ESCO2 paralogs acetylate the cohesin complex subunit SMC3 to regulate the separation of sister chromatids during mitosis and meiosis. Missense mutations within the acetyltransferase domain of these proteins correlate with diseases, including endometrial cancers and Roberts syndrome...
December 16, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27796307/kat2a-kat2b-targeted-acetylome-reveals-a-role-for-plk4-acetylation-in-preventing-centrosome-amplification
#18
Marjorie Fournier, Meritxell Orpinell, Cédric Grauffel, Elisabeth Scheer, Jean-Marie Garnier, Tao Ye, Virginie Chavant, Mathilde Joint, Fumiko Esashi, Annick Dejaegere, Pierre Gönczy, László Tora
Lysine acetylation is a widespread post-translational modification regulating various biological processes. To characterize cellular functions of the human lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), we determined their acetylome by shotgun proteomics. One of the newly identified KAT2A/2B substrate is polo-like kinase 4 (PLK4), a key regulator of centrosome duplication. We demonstrate that KAT2A/2B acetylate the PLK4 kinase domain on residues K45 and K46. Molecular dynamics modelling suggests that K45/K46 acetylation impairs kinase activity by shifting the kinase to an inactive conformation...
October 31, 2016: Nature Communications
https://www.readbyqxmd.com/read/27785912/structural-and-biochemical-characterization-of-acinetobacter-spp-aminoglycoside-acetyltransferases-highlights-functional-and-evolutionary-variation-among-antibiotic-resistance-enzymes
#19
Peter J Stogios, Misty Lee Kuhn, Elena Evdokimova, Melissa Law, Patrice Courvalin, Alexei Savchenko
Modification of aminoglycosides by N-acetyltransferases (AACs) is one of the major mechanisms of resistance to these antibiotics in human bacterial pathogens. More than fifty enzymes belonging to the AAC(6') subfamily have been identified in Gram-negative and Gram-positive clinical isolates. Our understanding of the molecular function and evolutionary origin of these resistance enzymes remains incomplete. Here we report the structural and enzymatic characterization of AAC(6')-Ig and AAC(6')-Ih from Acinetobacter spp...
October 27, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27783928/insight-into-the-3d-structure-and-substrate-specificity-of-previously-uncharacterized-gnat-superfamily-acetyltransferases-from-pathogenic-bacteria
#20
Karolina A Majorek, Tomasz Osinski, David T Tran, Alina Revilla, Wayne F Anderson, Wladek Minor, Misty L Kuhn
Members of the Gcn5-related N-acetyltransferase (GNAT) superfamily catalyze the acetylation of a wide range of small molecule and protein substrates. Due to their abundance in all kingdoms of life and diversity of their functions, they are implicated in many aspects of eukaryotic and prokaryotic physiology. Although numerous GNATs have been identified thus far, many remain structurally and functionally uncharacterized. The elucidation of their structures and functions is critical for broadening our knowledge of this diverse and important superfamily...
January 2017: Biochimica et Biophysica Acta
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