期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 29, 页码 16992-17002出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1914866117
关键词
EZH2; gene activation; transcriptional activation domain; phosphorylation; p300
资金
- Welch Foundation [I-1790, I-1304]
- Cancer Prevention and Research Institute of Texas [R1119]
- Rita Allen Foundation
- UT Southwestern Medical Center Endowed Scholar fund
- NIH [GM114576, GM121662, GM136308]
- American Heart Association [16POST30700004]
- Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research
- DOE Office of Science [DE-AC02-06CH11357]
- Office of Science, Office of Basic Energy Sciences, of the US DOE [DE-AC02-05CH11231]
- US DOE, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- NIH, National Institute of General Medical Sciences (NIGMS)
- DOE Biological and Environmental Research Integrated Diffraction Analysis Technologies program
- NIGMS [P30 GM124169-01]
- [P41GM103393]
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 trimethy-lation, 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 re-pressor 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 transcrip-tion 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 en-tirely sequestered. The EZH2 TAD can be unlocked by cancer -specific EZH2 phosphorylation events to undergo structural tran-sitions 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 correspond-ing 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 con-text of the EZH2 TAD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据