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Yoshihiro Nakatani - One of the best experts on this subject based on the ideXlab platform.
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regulation of histone Acetyltransferases p300 and pcaf by the bhlh protein twist and adenoviral oncoprotein e1a
Cell, 1999Co-Authors: Yasuo Hamamori, Yoshihiro Nakatani, Vasily Ogryzko, Vittorio Sartorelli, Pier Lorenzo Puri, Jean Y J Wang, Larry KedesAbstract:Abstract Histone Acetyltransferases (HAT) play a critical role in transcriptional control by relieving repressive effects of chromatin, and yet how HATs themselves are regulated remains largely unknown. Here, it is shown that Twist directly binds two independent HAT domains of Acetyltransferases, p300 and p300/CBP–associated factor (PCAF), and directly regulates their HAT activities. The N terminus of Twist is a primary domain interacting with both Acetyltransferases, and the same domain is required for inhibition of p300-dependent transcription by Twist. Adenovirus E1A protein mimics the effects of Twist by inhibiting the HAT activities of p300 and PCAF. These findings establish a cogent argument for considering the HAT domains as a direct target for Acetyltransferase regulation by both a cellular transcription factor and a viral oncoprotein.
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regulation of activity of the transcription factor gata 1 by acetylation
Nature, 1998Co-Authors: Joa Oyes, P G H Yfield, Yoshihiro Nakatani, Vasily OgryzkoAbstract:Modification of histones, DNA-binding proteins found in chromatin, by addition of acetyl groups occurs to a greater degree when the histones are associated with transcriptionally active DNA1,2. A breakthrough in understanding how this acetylation is mediated was the discovery that various transcriptional co-activator proteins have intrinsic histone Acetyltransferase activity (for example, Gcn5p (ref. 3), PCAF4, TAFII250 (ref. 5) and p300/CBP6,7). These Acetyltransferases also modify certain transcription factors (TFIIEβ, TFIIF, EKLF and p53 (8–10)). GATA-1 is an important transcription factor in the haematopoietic lineage11 and is essential for terminal differentiation of erythrocytes and megakaryocytes12,13. It is associated in vivo with the Acetyltransferase p300/CBP14. Here we report that GATA-1 is acetylated in vitro by p300. This significantly increases the amount of GATA-1 bound to DNA and alters the mobility of GATA-1–DNA complexes, suggestive of a conformational change in GATA-1. GATA-1 is also acetylated in vivo and acetylation directly stimulates GATA-1-dependent transcription. Mutagenesis of important acetylated residues shows that there is a relationship between the acetylation and in vivo function of GATA-1. Wepropose that acetylation of transcription factors can alter interactions between these factors and DNA and among different transcription factors, and is an integral part of transcription and differentiation processes.
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the histone Acetyltransferase activity of human gcn5 and pcaf is stabilized by coenzymes
Journal of Biological Chemistry, 1997Co-Authors: Julio E Herrera, Yoshihiro Nakatani, Michael Bergel, Xiangjiao Yang, Michael BustinAbstract:Here we report that PCAF and human GCN5, two related type A histone Acetyltransferases, are unstable enzymes that under the commonly used assay conditions are rapidly and irreversibly inactivated. In addition, we report that free histone H1, although not acetylated in vivo, is a preferred and convenient in vitro substrate for the study of PCAF, human GCN5, and possibly other type A histone Acetyltransferases. Using either histone H1 or histone H3 as substrates, we find that preincubation with either acetyl-CoA or CoA stabilizes the Acetyltransferase activities of PCAF, human GCN5 and an enzymatically active PCAF deletion mutant containing the C-terminal half of the protein. The stabilization requires the continuous presence of coenzyme, suggesting that the Acetyltransferase-coenzyme complexes are stable, while the isolated apoenzymes are not. Human GCN5 and the N-terminal deletion mutant of PCAF are stabilized equally well by preincubation with either CoA or acetyl-CoA, while intact PCAF is better stabilized by acetyl-CoA than by CoA. Intact PCAF, but not the N-terminal truncation mutant or human GCN5, is autoacetylated. These findings raise the possibility that the intracellular concentrations of the coenzymes affect the stability and therefore the nuclear activity of these Acetyltransferases.
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nuclear receptor coactivator actr is a novel histone Acetyltransferase and forms a multimeric activation complex with p caf and cbp p300
Cell, 1997Co-Authors: Hongwu Chen, Martin L. Privalsky, Yoshihiro Nakatani, Richard J Lin, Louis R Schiltz, Debabrata Chakravarti, Alyssa Nash, Laszlo Nagy, Ronald M EvansAbstract:Abstract We report here the identification of a novel cofactor, ACTR, that directly binds nuclear receptors and stimulates their transcriptional activities in a hormone- dependent fashion. ACTR also recruits two other nuclear factors, CBP and P/CAF, and thus plays a central role in creating a multisubunit coactivator complex. In addition, and unexpectedly, we show that purified ACTR is a potent histone Acetyltransferase and appears to define a distinct evolutionary branch to this recently described family. Thus, hormonal activation by nuclear receptors involves the mutual recruitment of at least three classes of histone Acetyltransferases that may act cooperatively as an enzymatic unit to reverse the effects of histone deacetylase shown to be part of the nuclear receptor corepressor complex.
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the transcriptional coactivators p300 and cbp are histone Acetyltransferases
Cell, 1996Co-Authors: Vasily Ogryzko, Louis R Schiltz, Valya Russanova, Bruce H Howard, Yoshihiro NakataniAbstract:p300/CBP is a transcriptional adaptor that integrates signals from many sequence-specific activators via direct interactions. Various cellular and viral factors target p300/CBP to modulate transcription and/or cell cycle progression. One such factor, the cellular p300/CBP associated factor (PCAF), possesses intrinsic histone Acetyltransferase activity. Here, we demonstrate that p300/CBP is not only a transcriptional adaptor but also a histone Acetyltransferase. p300/CBP represents a novel class of Acetyltransferases in that it does not have the conserved motif found among various other Acetyltransferases. p300/CBP acetylates all four core histones in nucleosomes. These observations suggest that p300/CBP acetylates nucleosomes in concert with PCAF.
C D Allis - One of the best experts on this subject based on the ideXlab platform.
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solution structure of the catalytic domain of gcn5 histone Acetyltransferase bound to coenzyme a
Nature, 1999Co-Authors: Yingxi Lin, C D Allis, Jianxin Zhou, C M Fletcher, Gerhard WagnerAbstract:Gene transcription requires the release of inactive DNA from its packaging of histone proteins. Following the discovery of the first transcription-associated histone Acetyltransferase, tetrahymena GCN5, it was shown that yeast GCN5 is recruited to the promoter and causes hyper-acetylation of histones and transcriptional activation of target genes, establishing a direct connection between histone acetylation and transcriptional activation. Many other important transcription regulators have been found to have histone Acetyltransferase activity, including TAFII230/250, p300/CBP and its associated factor PCAF. Here we present the solution structure of the catalytic domain of tGCN5 (residues 47-210) in complex with coenzyme A. The structure contains two domains; the amino-terminal domain is similar to those of other GCN5-related N-Acetyltransferases but the carboxy-terminal domain is not. Coenzyme A binds in a deep hydrophobic pocket between the two domains. Chemical shift changes upon titration with histone H3 peptides indicate a binding site at the domain boundary opposite to the coenzyme A site. The structural data indicate a single-step acetyl-transfer reaction mechanism catalysed by a hydrogen bond to the backbone amide group of leucine 126 and the side-chain carboxyl group of a conserved acidic residue.
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transcription linked acetylation by gcn5p of histones h3 and h4 at specific lysines
Nature, 1996Co-Authors: M H Kuo, James E Ownell, R E Sobel, Tamara A Ranalli, Richard G Cook, Diane G Edmondso, Sharo Y Roth, C D AllisAbstract:The yeast transcriptional adaptor, Gcn5p, is a catalytic subunit of a nuclear (type A) histone Acetyltransferase linking histone acetylation to gene activation. Here we report that Gcn5p acetylates histones H3 and H4 non-randomly at specific lysines in the amino-terminal domains. Lysine 14 of H3 and lysines 8 and 16 of H4 are highly preferred acetylation sites for Gcn5p. We also demonstrate that lysine 9 is the preferred position of acetylation in newly synthesized yeast H3 in vivo. This finding, along with the fact that lysines 5 and 12 in H4 are predominant acetylation sites during chromatin assembly of many organisms, indicates that Gcn5p acetylates a distinct set of lysines that do not overlap with those sites characteristically used by type B histone Acetyltransferases for histone deposition and chromatin assembly.
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tetrahymena histone Acetyltransferase a a homolog to yeast gcn5p linking histone acetylation to gene activation
Cell, 1996Co-Authors: James E Ownell, Tamara A Ranalli, Diane G Edmondso, Sharo Y Roth, J Zhou, R Kobayashi, C D AllisAbstract:We report the cloning of a transcription-associated histone Acetyltransferase type A(HAT A). This Tetrahymena enzyme is strikingly homologous to the yeast protein Gcn5, a putative transcriptional adaptor, and we demonstrate that recombinant Gcn5p possesses HAT activity. Both the ciliate enzyme and Gcn5p contain potential active site residues found in other Acetyltransferases and a highly conserved bromodomain. The presence of this domain in nuclear A-type HATs, but not in cytoplasmic B-type HATs, suggests a mechanism whereby HAT A is directed to chromatin to facilitate transcriptional activation. These findings shed light on the biochemical function of the evolutionarily conserved Gcn5p-Ada complex, directly linking histone acetylation to gene activation, and indicate that histone acetylation is a targeted phenomenon.
Federico Pietrocola - One of the best experts on this subject based on the ideXlab platform.
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spermidine induces autophagy by inhibiting the Acetyltransferase ep300
Cell Death & Differentiation, 2015Co-Authors: Federico Pietrocola, Sylvie Lachkar, David Enot, Mireia Nisosantano, J Bravosan M Pedro, Valentina SicaAbstract:Several natural compounds found in health-related food items can inhibit Acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the Acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two Acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(α)-Acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the Acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors.
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Spermidine induces autophagy by inhibiting the Acetyltransferase EP300.
Cell death and differentiation, 2014Co-Authors: Federico Pietrocola, Sylvie Lachkar, David Enot, Valentina Sica, Mireia Niso-santano, J M Bravo-san Pedro, Valentina Izzo, Maria Chiara Maiuri, Frank Madeo, Guillermo MariñoAbstract:Several natural compounds found in health-related food items can inhibit Acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the Acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two Acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(α)-Acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the Acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors.
Ronen Marmorstein - One of the best experts on this subject based on the ideXlab platform.
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molecular basis for cohesin acetylation by establishment of sister chromatid cohesion n Acetyltransferase esco1
Journal of Biological Chemistry, 2016Co-Authors: Yadilette Riveracolon, Andrew Maguire, Glen Liszczak, Adam S Olia, Ronen MarmorsteinAbstract:Abstract Protein acetylation is a prevalent posttranslational modification that is regulated by diverse Acetyltransferase enzymes. While 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. Despite their biological importance, the mechanisms underlying acetylation by the ESCO proteins are not understood. Here, we report the X-ray crystal structure of the highly conserved zinc finger-Acetyltransferase moiety of ESCO1 with accompanying structure-based mutagenesis and biochemical characterization. We find that the ESCO1Acetyltransferase core is structurally homologous to the Gcn5 HAT, but contains unique additional features including a zinc finger and a ~40-residue loop region that appear to play roles in protein stability and SMC3 substrate binding. We identify key residues that play roles in substrate binding and catalysis, and rationalize the functional consequences of disease-associated mutations. Together, these studies reveal the molecular basis for SMC3 acetylation by ESCO1 and have broader implications for understanding the structure/function of non-histone Acetyltransferases.
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crystal structure of the histone Acetyltransferase domain of the human pcaf transcriptional regulator bound to coenzyme a
The EMBO Journal, 1999Co-Authors: Adrienne Clements, Shelley L. Berger, Lian Wang, J R Rojas, Raymond C Trievel, Ronen MarmorsteinAbstract:The human p300/CBP‐associating factor, PCAF, mediates transcriptional activation through its ability to acetylate nucleosomal histone substrates as well as transcriptional activators such as p53. We have determined the 2.3 A crystal structure of the histone Acetyltransferase (HAT) domain of PCAF bound to coenzyme A. The structure reveals a central protein core associated with coenzyme A binding and a pronounced cleft that sits over the protein core and is flanked on opposite sides by the N‐ and C‐terminal protein segments. A correlation of the structure with the extensive mutagenesis data for PCAF and the homologous yeast GCN5 protein implicates the cleft and the N‐ and C‐terminal protein segments as playing an important role in histone substrate binding, and a glutamate residue in the protein core as playing an essential catalytic role. A structural comparison with the coenzyme‐bound forms of the related N ‐Acetyltransferases, HAT1 (yeast histone Acetyltransferase 1) and SmAAT ( Serratia marcescens aminoglycoside 3‐ N ‐Acetyltransferase), suggests the mode of substrate binding and catalysis by these enzymes and establishes a paradigm for understanding the structure–function relationships of other enzymes that acetylate histones and transcriptional regulators to promote activated transcription.
Michael L Goldberg - One of the best experts on this subject based on the ideXlab platform.
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two putative Acetyltransferases san and deco are required for establishing sister chromatid cohesion in drosophila
Current Biology, 2003Co-Authors: Byron C Williams, Carrie M Garrettengele, Zexiao Li, Erika V Williams, Elizabeth D Rosenman, Michael L GoldbergAbstract:Abstract Background: Sister chromatid cohesion is needed for proper alignment and segregation of chromosomes during cell division. Chromatids are linked by the multiprotein cohesin complex, which binds to DNA during G 1 and then establishes cohesion during S phase DNA replication. However, many aspects of the mechanisms that establish and maintain cohesion during mitosis remain unclear. Results: We found that mutations in two evolutionarily conserved Drosophila genes, san (s eparation an xiety ) and deco (D rosophila eco 1 ), disrupt centromeric sister chromatid cohesion very early in division. This failure of sister chromatid cohesion does not require separase and is correlated with a failure of the cohesin component Scc1 to accumulate in centromeric regions. It thus appears that these mutations interfere with the establishment of centromeric sister chromatid cohesion. Secondary consequences of these mutations include activation of the spindle checkpoint, causing metaphase delay or arrest. Some cells eventually escape the block but incur many errors in anaphase chromosome segregation. Both san and deco are predicted to encode Acetyltransferases, which transfer acetyl groups either to internal lysine residues or to the N terminus of other proteins. The San protein is itself acetylated, and it associates with the Nat1 and Ard1 subunits of the NatA Acetyltransferase. Conclusions: At least two diverse Acetyltransferases play vital roles in regulating sister chromatid cohesion during Drosophila mitosis.
