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Crosstalk Between Acetylation and Ubiquitination Contributes to PRMT1 methyltransferase Homeostasis

ABSTRACT: PRMT1 plays pivotal roles in normal and disease biology. Understanding its regulation is crucial for therapeutic targeting. We demonstrate that p300-mediated acetylation of PRMT1 at K228 triggers degradation via FBXL17-dependent ubiquitination at K145. Using mass spectrometry, cellular biochemistry, and genetic code-expansion, we reveal the crosstalk between acetylation and ubiquitination in PRMT1 homeostasis, highlighting mechanisms governing protein stability. This study results in Identification of K228 acetylation and K145 ubiquitination sites on PRMT1, FBXL17 as the E3 ligase mediating PRMT1 ubiquitination and interdependence of p300 acetylation and FBXL17 ubiquitination in PRMT1 degradation. We have used Co-IP MS to look for protein-protein interactions (e.g., PRMT1-FBXL17/p300 complexes), IP-MS to map Acetylation/ubiquitination sites (PRMT1 post-translational modifications) and genetic code-expansion (site-specific incorporation of acetyl-lysine)

ORGANISM(S): Homo sapiens

PROVIDER: GSE304181 | GEO | 2026/07/31

REPOSITORIES: GEO

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Homo sapiens

Project description:IP-MS

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FBXO7 Ubiquitinates PRMT1 to Suppress Serine Synthesis and Tumor Growth in Hepatocellular Carcinoma

Project description:FBXO7 directly interacts with PRMT1, leading to the lysine 37 ubiquitination and subsequent degradation of PRMT1.

2023-08-31 | PXD045015 |

Acetylation of the activated glucocorticoid receptor facilitates its proteasomal degradation thereby limiting hormonal signaling

Project description:The glucocorticoid (GC) receptor (GR) is a ligand-induced transcription factor regulating metabolism and inflammation. While homologous downregulation of ligand-bound GR limits the response, it also reduces hormone responsiveness resulting in glucocorticoid resistance. Regulatory mechanisms that refine this equilibrium are less understood. Here, we have identified seven lysine acetylation sites in the amino terminal domain of GR, lysine 154 within the regulatory AF-1 region being the dominant acetyl-acceptor. GR-Lys154 acetylation is mediated by p300/CBP in an exclusively agonist-induced manner and correlates with nuclear translocation and transcriptional activity. GR-Lys154 acetylation is removed by the NAD+ dependent deacetylase, SIRT1, indicating dynamic regulation of this mark. Notably, agonist-binding to both the wild type and acetylation-deficient mutant GR elicits similar short-term target gene expression. In contrast, upon extended treatment, the acetylation-deficient mutant shows impaired ubiquitination and higher protein stability with a concomitant increase in chromatin association and transactivation. Taken together, p300/CBP and SIRT1 fine-tune glucocorticoid response by siphoning acetylated GR for proteasomal degradation while GR deacetylation sustains the transcriptional cascade for prolonged periods.

2024-01-16 | GSE236739 | GEO

CBP/P300 Function in Repression as well as Activation Regulated by Adenovirus Small E1A [IMR90_Input]

Project description:Oncogenic transformation by adenovirus small e1a depends on simultaneous interactions with P300/CBP and RB proteins. To understand why, experiments with structure-based e1a mutants were analyzed with RNA- and ChIP-seq. The results indicate that e1a displaces RBs from E2F activation domains and, by promoting P300 acetylation of RB1 K873/K874, locks them into a repressing conformation that interacts with repressive chromatin modifying enzymes. e1a then delivers these repressing p300-e1a-RB1 complexes to cell genes that have unusually high P300 association with the gene body, enriched in genes of the TGFb-, TNF-, and IL1-signaling pathways. The P300-e1a-RB complex condenses chromatin, dependent on HDAC activity, P300 lysine acetylase activity, the P300 bromodomain, and acetylation of RB K873/K874 and e1a K239, contributing to repression of host genes that would otherwise inhibit cell cycling. The data suggest why e1a must bind P300/CBP as well as RBs for oncogenic transformation and why a trimeric P300-e1a-RB1 complex is required. Chromatin IP background Input DNA for ChIP-seq normalization

2014-08-15 | E-GEOD-59692 | biostudies-arrayexpress

Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer (RNA-Seq)

Project description:Prostate cancer (PCa) is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancerPCa. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers, leading to stronger suppression of oncogenic transcription more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancerPCa, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as an key epigenetic marker of enhancer addiction and establish support dual p300/CBP degradation as a promising therapeutic strategypy for enhancer-driven cancers.

2025-06-26 | GSE255133 | GEO

Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer (ChIP-Seq)

2025-06-26 | GSE255132 | GEO

Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer (ATAC-Seq)

2025-06-26 | GSE255131 | GEO

Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer

Project description:Prostate cancer is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancer. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancer, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as a key epigenetic marker of enhancer addiction and support dual p300/CBP degradation as a promising therapy for enhancer-driven cancers.

2025-07-28 | PXD065228 | Pride

Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer

2025-07-28 | PXD065292 | Pride

Ubiquitin-dependent turnover of MYC promotes loading of the PAF complex on RNA Polymerase II to drive transcriptional elongation (ChIP-seq)

Project description:The MYC transcription factor is an unstable protein and its turnover is controlled by the ubiquitin system. Ubiquitination enhances MYC-dependent transactivation, but the underlying mechanism remains unresolved. Here we show that proteasomal turnover of MYC is dispensable for recruitment of RNA polymerase II (RNAPII), but is required to promote transcriptional elongation at MYC target genes. Degradation of MYC stimulates histone acetylation and recruitment of BRD4 and P-TEFb to target promoters, leading to phosphorylation of RNAPII CTD and the release of elongating RNAPII. In the absence of degradation, the RNA polymerase II-associated factor (PAF) complex associates with MYC via interaction of its CDC73 subunit with a conserved domain in the amino-terminus of MYC ("MYC box I"), suggesting that a MYC/PAF complex is an intermediate in transcriptional activation. Since histone acetylation depends on a second highly conserved domain in MYCs amino-terminus ("MYC box II"), we propose that both domains co-operate to transfer elongation factors onto paused RNAPII. ChIP-Seq experiments for MYC-HA (HA-IP) and RNAPII (total,Ser2p,Ser5p) performed in IMEC primary breast epithelial cells. Input-samples were sequenced as controls. The following antibodies were used: HA (Abcam; ab 9110)/ total RNAPII (Santa Cruz; sc-899x)/ Ser2p RNAPII (Abcam; ab 5095)/ Ser5p RNAPII (Covance; MMS-128P)

2016-01-04 | E-GEOD-70001 | biostudies-arrayexpress

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