The transcriptional coactivator MAML1 regulates p300 autoacetylation and HAT activity

Hansson, Magnus L.; Popko-Scibor, Anita E.; Ribeiro, Mariana Saint Just; Dancy, Beverley M.; Lindberg, Mikael; Cole, Philip A.; Wallberg, Annika E.

doi:10.1093/nar/gkp163

Cited by 56 publications

(56 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Functionally, the autoacetylation of p300 causes a conformational change within the p300 HAT domain that is detected by increased accessibility to proteinase K and promotes transcriptional activation (41). The autoacetylation of p300 also occurs beyond the autoacetylation loop, because p300 can be autoacetylated even when the autoacetylation loop is deleted (42). We suggest that, within the nonacetylated CBP, the acetyl-binding pocket of the bromodomain is blocked by another region of CBP.…”

Section: Discussionmentioning

confidence: 88%

Binding of the histone chaperone ASF1 to the CBP bromodomain promotes histone acetylation

Das

Roy

Namjoshi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The multifunctional Creb-binding protein (CBP) protein plays a pivotal role in many critical cellular processes. Here we demonstrate that the bromodomain of CBP binds to histone H3 acetylated on lysine 56 (K56Ac) with higher affinity than to its other monoacetylated binding partners. We show that autoacetylation of CBP is critical for the bromodomain-H3 K56Ac interaction, and we propose that this interaction occurs via autoacetylation-induced conformation changes in CBP. Unexpectedly, the bromodomain promotes acetylation of H3 K56 on free histones. The CBP bromodomain also interacts with the histone chaperone anti-silencing function 1 (ASF1) via a nearby but distinct interface. This interaction is necessary for ASF1 to promote acetylation of H3 K56 by CBP, indicating that the ASF1-bromodomain interaction physically delivers the histones to the histone acetyl transferase domain of CBP. A CBP bromodomain mutation manifested in Rubinstein-Taybi syndrome has compromised binding to both H3 K56Ac and ASF1, suggesting that these interactions are important for the normal function of CBP. C hromatin is the physiological template for all genomic processes. The histone proteins that package the DNA into chromatin are subject to posttranslational modifications, including acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, that serve to regulate DNA-templated phenomena such as transcription, replication, repair, and recombination (1). Many histone posttranslational modifications mediate their function by interacting specifically with and recruiting "reader" modules of multifunctional proteins, which often themselves have activities that subsequently further modify the chromatin structure to make the DNA either more or less accessible. For example, the bromodomain is the specific reader module for acetylated lysines on histones and nonhistone proteins (reviewed in ref.2), where acetylation is one of the most abundant posttranslational modifications in human cells.The bromodomain is found in many transcriptional coregulators and histone-modifying complexes, including histone acetyl transferases (HATs), enzymes that themselves mediate acetylation. Structural studies have revealed that bromodomains have a conserved structural fold that consists of a left-handed four-helix bundle and two interspersed ZA and BC loops which constitute the active acetyl lysine-binding pocket (3). Despite this conserved overall structure, different bromodomains recognize distinct acetylated lysines in different proteins because the specific amino acid residues within the loops of each bromodomain are critical for determining the acetyl lysine-binding specificity (4, 5).The general theme for bromodomain function is that they serve to anchor the bromodomain-containing protein to acetylated chromatin templates or to acetylated transcriptional activators. For example, the bromodomains of the yeast ATP-dependent nucleosome remodeler Swi2 and the HAT GCN5 are required for anchoring these chromatin-modifying complexes to acetylated c...

show abstract

Section: Discussionmentioning

confidence: 88%

Binding of the histone chaperone ASF1 to the CBP bromodomain promotes histone acetylation

Das

Roy

Namjoshi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…However, the mechanistic details describing the role of p300 in Notch-mediated transcription are not clear. Although several reports have shown that Maml1 is acetylated by p300 on multiple lysine residues, no activity has yet been attributed to acetylation of Maml, and it is not clear in which step of Notch-mediated transcription process p300 is involved (15,23). Fryer and colleagues demonstrated that p300 was localized on the HES1 promoter prior to activation of Notch, indicating that p300 may play a role in assembly and/or modulation of the Notch transcriptional complex (14).…”

Section: P300 Acetylates Maml1 To Recruit Nack Leading To Transcriptmentioning

confidence: 99%

Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription

et al. 2017

View full text Add to dashboard Cite

Although it has long been appreciated that p300 acts as a critical Notch coactivator, the mechanistic details of p300 in Notch-mediated transcription remain unclear. We previously demonstrated that PEAK1-related kinase activating pseudokinase 1 (NACK), also known as SGK223, is a critical coactivator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription. NACK is recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2. Simultaneous inhibition of p300/ CBP and Notch has a synergistic effect in esophageal adenocarcinoma. In summary, this study provides a deeper mechanistic understanding of the assembly of the Notch transcriptional complex and provides rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers. Cancer Res; 77(16); 4228-37. Ó2017 AACR.

show abstract

“…Recent experimental evidence suggests HATs can be auto-acetylated, and these complexes can be recruited to many classes of DNA binding transcription factors (Blanco-Garcia et al 2009;Hansson et al 2009;Albaugh et al 2011;Yang et al 2012a,b). Indeed, HDAC inhibition is implicated in EP300 hyperacetylation, and its auto-acetylation has been shown to increase protein stability and prevent proteasomal degradation (Kim et al 2010;Jain et al 2012).…”

Section: Distinct Deacetylation Signals In Reanalyzed Datamentioning

confidence: 99%

Vascular histone deacetylation by pharmacological HDAC inhibition

et al. 2014

View full text Add to dashboard Cite

HDAC inhibitors can regulate gene expression by post-translational modification of histone as well as nonhistone proteins. Often studied at single loci, increased histone acetylation is the paradigmatic mechanism of action. However, little is known of the extent of genome-wide changes in cells stimulated by the hydroxamic acids, TSA and SAHA. In this article, we map vascular chromatin modifications including histone H3 acetylation of lysine 9 and 14 (H3K9/14ac) using chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq). Since acetylation-mediated gene expression is often associated with modification of other lysine residues, we also examined H3K4me3 and H3K9me3 as well as changes in CpG methylation (CpG-seq). RNA sequencing indicates the differential expression of ∼30% of genes, with almost equal numbers being up- and down-regulated. We observed broad deacetylation and gene expression changes conferred by TSA and SAHA mediated by the loss of EP300/CREBBP binding at multiple gene promoters. This study provides an important framework for HDAC inhibitor function in vascular biology and a comprehensive description of genome-wide deacetylation by pharmacological HDAC inhibition.

show abstract

The transcriptional coactivator MAML1 regulates p300 autoacetylation and HAT activity

Cited by 56 publications

References 35 publications

Binding of the histone chaperone ASF1 to the CBP bromodomain promotes histone acetylation

Binding of the histone chaperone ASF1 to the CBP bromodomain promotes histone acetylation

Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription

Vascular histone deacetylation by pharmacological HDAC inhibition

Contact Info

Product

Resources

About