Design, Synthesis, and Biological Evaluation of a Small‐Molecule Inhibitor of the Histone Acetyltransferase Gcn5

Biel, Markus; Kretsovali, Androniki; Karatzali, Efthymia; Papamatheakis, Joseph; Giannis, Athanassios

doi:10.1002/anie.200453879

Cited by 149 publications

(88 citation statements)

References 28 publications

(12 reference statements)

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“…In line with this, we also observed a reduction of H1.4K34ac signal upon treatment of cells with an inhibitor of GCN5, butyrolactone 3 (Fig. 1E, right panel; Biel et al 2004), and GCN5-containing SAGA and ATAC complexes purified from HeLa cells acetylated H1.4K34 in our in vitro HAT assays ( Fig. 1F; Supplemental Fig.…”

Section: H14k34 Is a Gcn5 Targetsupporting

confidence: 81%

A dual role of linker histone H1.4 Lys 34 acetylation in transcriptional activation

Kamieniarz¹,

Izzo²,

Dundr³

et al. 2012

Genes Dev.

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The linker histone H1 is a key player in chromatin organization, yet our understanding of the regulation of H1 functions by post-translational modifications is very limited. We provide here the first functional characterization of H1 acetylation. We show that H1.4K34 acetylation (H1.4K34ac) is mediated by GCN5 and is preferentially enriched at promoters of active genes, where it stimulates transcription by increasing H1 mobility and recruiting a general transcription factor. H1.4K34ac is dynamic during spermatogenesis and marks undifferentiated cells such as induced pluripotent stem (iPS) cells and testicular germ cell tumors. We propose a model for H1.4K34ac as a novel regulator of chromatin function with a dual role in transcriptional activation.

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Section: H14k34 Is a Gcn5 Targetsupporting

confidence: 81%

A dual role of linker histone H1.4 Lys 34 acetylation in transcriptional activation

Kamieniarz¹,

Izzo²,

Dundr³

et al. 2012

Genes Dev.

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“…To confirm the assumption that auxin-induced transcription is controlled by histone acetylation and deacetylation, we monitored the expression of auxin-responsive marker genes in the absence and presence of the broad-spectrum HDAC inhibitor trichostatin A (TSA) 40,41 or the GCN5-specific HAT inhibitor, g-butyrolactone 42 . To ensure equal exposure of the plant cells to the additives, wild-type (WT) mesophyll protoplasts were prepared and incubated with low concentrations of TSA or g-butyrolactone, prior to subjection to an additional auxin or mock treatment.…”

Section: Resultsmentioning

confidence: 99%

“…It has been demonstrated to efficiently target aa within the catalytic active site of the mammalian GCN5 enzyme 42 . As these aa are conserved within the homologous yeast and Arabidopsis proteins (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

The Arabidopsis transcription factor bZIP11 activates auxin-mediated transcription by recruiting the histone acetylation machinery

2014

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In higher plants, the hormone auxin orchestrates a diverse array of developmental and environmental responses mainly exerted via transcriptional control. In its absence, auxin-mediated transcription is postulated to be repressed by histone deacetylases, which convert chromatin into a highly packed inactive state. Here we present a converse mechanism where Arabidopsis bZIP11-related basic leucine zipper (bZIP) transcription factors interact via an amino-terminal activation domain with ADA2b adapter proteins to recruit the histone acetylation machinery to specific auxin-responsive genes. Gain, loss-of-function and pharmacological approaches as well as chromatin immunoprecipitation experiments addressing various components of the recruitment and acetylation machinery substantiate the proposed mechanism. Importantly, G-box-related cis-elements, frequently found in auxininduced promoters, are shown to bind bZIP11-related bZIPs and to function as quantitative modulators of auxin-induced transcription. In conclusion, we describe a regulatory activation mechanism that serves as a rheostat to modulate auxin-mediated responses.

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“…Cys 177 is believed to form hydrogen bonds that bind acetyl-CoA in close proximity with the histone substrate and to Glu 173 , allowing catalysis of transfer of the acetyl group onto the lysine side chain of the histone (9,48). Therefore, Cys 177 is probably the amino acid whose side chain reacts with isothiazolones to form a new covalent bond with consequent loss of HAT catalytic activity.…”

Section: Discussionmentioning

confidence: 99%

Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity

Stimson

Rowlands

Newbatt

et al. 2005

Molecular Cancer Therapeutics

209

128

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Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by two classes of enzyme, histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulated HAT and HDAC activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anticancer agents. Several HDAC inhibitors have been described; however, few inhibitors of HATs have been disclosed. Following a FlashPlate highthroughput screen, we identified a series of isothiazolonebased HAT inhibitors. Thirty-five N-substituted analogues inhibited both p300/cyclic AMP -responsive element binding protein -binding protein -associated factor (PCAF) and p300 (1 to >50 Mmol/L, respectively) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to >50 Mmol/L). CCT077791 and CCT077792 decreased cellular acetylation in a time-dependent manner (2 -48 hours of exposure) and a concentration-dependent manner (one to five times, 72 hours, 50% growth inhibition) in HCT116 and HT29 human colon tumor cell lines. CCT077791 reduced total acetylation of histones H3 and H4, levels of specific acetylated lysine marks, and acetylation of A-tubulin. Four and 24 hours of exposure to the compounds produced the same extent of growth inhibition as 72 hours of continuous exposure, suggesting that growth arrest was an early event. Chemical reactivity of these compounds, as measured by covalent protein binding and loss of HAT inhibition in the presence of DTT, indicated that reaction with thiol groups might be important in their mechanism of action. As one of the first series of small-molecule inhibitors of HAT activity, further analogue synthesis is being pursued to examine the potential scope for reducing chemical reactivity while maintaining HAT inhibition. [Mol Cancer Ther 2005;4(10):1521 -32]

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Design, Synthesis, and Biological Evaluation of a Small‐Molecule Inhibitor of the Histone Acetyltransferase Gcn5

Cited by 149 publications

References 28 publications

A dual role of linker histone H1.4 Lys 34 acetylation in transcriptional activation

A dual role of linker histone H1.4 Lys 34 acetylation in transcriptional activation

The Arabidopsis transcription factor bZIP11 activates auxin-mediated transcription by recruiting the histone acetylation machinery

Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity

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