Abstract B46: CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb Repressive complex 2 via a H3K27M-like mechanism
| Autor: | Natalia Khaltyan, Emily J. Rendleman, David C. Murray, Marc A. Morgan, Michal Ugarenko, Serdar E. Bulun, Kathryn A. Helmin, Jeffrey N. Savas, Caila Ryan, Edwin R. Smith, Benjamin D. Singer, Andrea Piunti, Bahar D. Yilmaz, Ryan Rickels, Ali Shilatifard |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Cancer Research. 80:B46-B46 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.pedca19-b46 |
| Popis: | Dysregulation of Polycomb Repressive Complex 2 (PRC2) function is a common feature of many cancer types, including both solid and hematologic malignancies. A number of chromosomal translocations involving Polycomb group proteins have been identified; however, the molecular function of these fusion proteins remains largely unexplored. Here we characterize two endometrial stromal sarcoma (ESS) associated fusion proteins: JAZF1-SUZ12 and MBTD1-CXORF67. We identify JAZF1 as a previously unreported subunit of the NuA4 complex, which when fused to SUZ12 creates a bridge between the NuA4 and PRC2 complexes. Intriguingly, the MBTD1-CXORF67 fusion binds to PRC2 and leads to strongly reduced levels of the PRC2 catalytic products H3K27me2/3. We demonstrate that this inhibitory function is mediated by the CXORF67 half of the fusion protein. Because of this striking property, we propose a new gene name: CATACOMB (CATalytic Antagosnist of polyCOMB; official gene name: EZHIP). We map CATACOMB’s inhibitory function to a short, highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles that of the oncogenic histone H3 lysine-27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. Finally, we show CATACOMB expression is silenced through DNA methylation and upon treatment with DNA demethylating agents, CATACOMB is expressed, binds to PRC2, and antagonizes its catalytic activity. In conclusion, we have identified an endogenous inducible gene, CATACOMB, which can regulate the catalytic activity of PRC2 and propose that such mechanism of regulation of histone modifications through the expression of antagonistic subunits may also exist for other histone-modifying enzyme complexes. Citation Format: Andrea Piunti, Edwin Smith, Marc Morgan, Michal Ugarenko, Natalia Khaltyan, Kathryn Helmin, Caila Ryan, David Murray, Ryan Rickels, Bahar Yilmaz, Emily Rendleman, Jeffrey Savas, Benjamin Singer, Serdar Bulun, Ali Shilatifard. CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb Repressive complex 2 via a H3K27M-like mechanism [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B46. |
| Databáze: | OpenAIRE |
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