ArticleProceedings of the National Academy of Sciences of the United States of America2020
A partially disordered region connects gene repression and activation functions of EZH2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 61 citations in OpenAlex.
- An EZH2-SREBP2 axis promotes cholesterol biosynthesis and represents a noncanonical vulnerability in tumorigenesis.Nature cell biology · 2026Article
- PVT1 lincRNA signals an androgen-dependent transcriptional activation program of oncogenes in prostate cancer cells.International journal of cancer · 2026Article
- The conserved N-terminal SANT1-binding domain (SBD) of EZH2 regulates PRC2 activity.Genes & development · 2026Article
- Epigenetic Regulation of Higher-Order Chromatin Structure (HOCS) and Its Implication in Human Diseases.Cancers · 2026Review
- Review
- Bifaceted functions of histone methyltransferases.Epigenomics · 2025Article
- An evolving landscape of PRC2-RNA interactions in chromatin regulation.Nature reviews. Molecular cell biology · 2025Review
- Multiple transactivation domains of EZH2 bind to the TAZ2 domain of p300 and stimulate the acetyltransferase function of p300.The Biochemical journal · 2025Article
- Treating human cancer by targeting EZH2.Genes & diseases · 2025Review
- EZH2,World journal of stem cells · 2025Article
- Conformational Analyses of the AHD1-UBAN Region of TNIP1 Highlight Key Amino Acids for Interaction with Ubiquitin.Biomolecules · 2025Article
- EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma.Neuro-oncology · 2025Article
- Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.Therapeutic advances in medical oncology · 2025Review
- EZH2 elicits CD8Communications biology · 2024Article
- Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma.Cell death & disease · 2024Article
- EZH2 PROTACs target EZH2- and FOXM1-associated oncogenic nodes, suppressing breast cancer cell growth.Oncogene · 2024Article
- The Rapid Evolution of De Novo Proteins in Structure and Complex.Genome biology and evolution · 2024Article
- Characterization of Intrinsically Disordered Proteins in Healthy and Diseased States by Nuclear Magnetic Resonance.Reviews on recent clinical trials · 2024Review
- SAP30 promotes breast tumor progression by bridging the transcriptional corepressor SIN3 complex and MLL1.The Journal of clinical investigation · 2023Article
- An EZH2-NF-κB regulatory axis drives expression of pro-oncogenic gene signatures in triple negative breast cancer.iScience · 2023Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which minimally requires two other subunits, EED and SUZ12, for enzymatic activity. EZH2 has been traditionally known to mediate histone H3K27 trimethylation, a hallmark of silent chromatin. Emerging evidence indicates that EZH2 also activates gene expression in cancer cells in a context distinct from canonical PRC2. The molecular mechanism underlying the functional conversion of EZH2 from a gene repressor to an activator is unclear. Here, we show that EZH2 harbors a hidden, partially disordered transactivation domain (TAD) capable of interacting with components of active transcription machinery, mimicking archetypal acidic activators. The EZH2 TAD comprises the SRM (Stimulation-Responsive Motif) and SANT1 (SWI3, ADA2, N-CoR, and TFIIIB 1) regions that are normally involved in H3K27 methylation. The crystal structure of an EZH2-EED binary complex indicates that the EZH2 TAD mediates protein oligomerization in a noncanonical PRC2 context and is entirely sequestered. The EZH2 TAD can be unlocked by cancer-specific EZH2 phosphorylation events to undergo structural transitions that may enable subsequent transcriptional coactivator binding. The EZH2 TAD directly interacts with the transcriptional coactivator and histone acetyltransferase p300 and activates gene expression in a p300-dependent manner in cells. The corresponding TAD may also account for the gene activation function of EZH1, the paralog of EZH2. Distinct kinase signaling pathways that are known to abnormally convert EZH2 into a gene activator in cancer cells can now be understood in a common structural context of the EZH2 TAD.
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