Live‐Cell Studies of p300/CBP Histone Acetyltransferase Activity and Inhibition

Dancy, Beverley M.; Crump, Nicholas T.; Peterson, Daniel J.; Mukherjee, Chandrani; Bowers, Erin M.; Ahn, Young Hoon; Yoshida, Minoru; Zhang, Jin; Mahadevan, Louis C.; Meyers, David J.; Boeke, Jef D.; Cole, Philip A.

doi:10.1002/cbic.201200381

Cited by 47 publications

(57 citation statements)

References 46 publications

(24 reference statements)

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“…To account for potential off-target effects of C646 we used C37 as a control, a compound very similar in structure to C646 but that shows no effect on CBP HAT activity (Bowers et al, 2010). C646 and related inhibitors have previously been shown to affect histone acetylation in Drosophila and mammalian cells within minutes (Crump et al, 2011; Dancy et al, 2012). To assess the immediate transcriptional response to CBP inhibition genome-wide, we performed precision run-on sequencing (PRO-seq) with S2 cells treated with C37 (control) or C646 for 10 min.…”

Section: Resultsmentioning

confidence: 99%

CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II

et al. 2017

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Summary Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here we identify a novel activity of the histone acetyltransferase p300/CBP in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in “dribbling” of Pol II from the pause site to positions further downstream, but impedes transcription through the +1 nucleosome genome-wide. Promoters strongly occupied by CBP and GAGA-factor have high levels of paused Pol II, a unique chromatin signature and are highly expressed regardless of cell type. Interestingly, CBP activity is rate-limiting for Pol II recruitment to these highly-paused promoters through an interaction with TFIIB, but for transit into elongation by histone acetylation at other genes. Thus, CBP directly stimulates both Pol II recruitment and the ability to traverse the first nucleosome, thereby promoting transcription of most genes.

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Section: Resultsmentioning

confidence: 99%

CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II

et al. 2017

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“…Thus, simply inducing a histone hyperacetylated state with HDACi does not adequately replace HAT activation, at least in certain functions (i.e., memory formation), likely reflecting the other potential roles of HAT (e.g., CBP). The indirect (HDAC inhibitor-mediated) activation of p300/ CBP HAT auto-acetylation, which stimulates HAT activity [36,216], could also contribute to the beneficial effects of HDACi. Thus, it seems essential to envisage direct stimulation of the HAT function, as a new therapeutic tool in neurodegenerative diseases; by directly targeting the remaining HAT(s), one could re-activate the deficient enzymatic function, as well as all the other related functions that are not typically considered using an HDACi strategy.…”

Section: Hat Activation Vs Hdac Inhibition As a Therapeutic Strategymentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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“…19 Inhibitors of p300/CBP HAT activity have been developed and are under investigation as therapeutics for a number of diseases. 5,10,14,22,23 Additional key p300/CBP domains include a well-characterized bromodomain that is just N-terminal to the HAT domain and can bind acetyl-Lys-containing peptides. The bromodomain is one of the most highly conserved domains in p300 and CBP, possessing 96% sequence identity.…”

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confidence: 99%

Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112

Zucconi

Luef

et al. 2016

Biochemistry

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The histone acetyltransferase (HAT) enzymes p300 and CBP are closely related paralogs that serve as transcriptional coactivators and have been found to be dysregulated in cancer and other diseases. p300/CBP is a multidomain protein and possesses a highly conserved bromodomain that has been shown to bind acetylated Lys residues in both proteins and various small molecules, including I-CBP112 and CBP30. Here we show that the ligand I-CBP112 can stimulate nucleosome acetylation up to 3-fold while CBP30 does not. Activation of p300/CBP by I-CBP112 is not observed with the isolated histone H3 substrate but requires a nucleosome substrate. I-CBP112 does not impact nucleosome acetylation by the isolated p300 HAT domain, and the effects of I-CBP112 on p300/CBP can be neutralized by CBP30, suggesting that I-CBP112 likely allosterically activates p300/CBP through bromodomain interactions. Using mass spectrometry and Western blots, we have found that I-CBP112 particularly stimulates acetylation of Lys18 of histone H3 (H3K18) in nucleosomes, an established in vivo site of p300/CBP. In addition, we show that I-CBP112 enhances H3K18 acetylation in acute leukemia and prostate cancer cells in a concentration range commensurate with its antiproliferative effects. Our findings extend the known pharmacology of bromodomain ligands in the regulation of p300/CBP and suggest a novel approach to modulating histone acetylation in cancer.

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Live‐Cell Studies of p300/CBP Histone Acetyltransferase Activity and Inhibition

Cited by 47 publications

References 46 publications

CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II

CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112

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