Discovery and Characterization of a Cellularly Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7
| Autor: | Kelsey N. Lamb, Daniel Bsteh, Stephen V. Frye, Hagar F. Moussa, Lindsey I. James, Sarah N. Dishman, Jacob I. Stuckey, Benjamin Z. Stanton, Huitao Fan, Jacqueline L. Norris, Dongxu Li, Mark T. Bedford, Cari A. Sagum, Terry P. Kenakin, Dmitri Kireev, Gang Greg Wang, Oliver Bell, Jingkui Wang, Stephanie H. Cholensky |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Allosteric modulator 010405 organic chemistry RNA macromolecular substances 01 natural sciences 0104 chemical sciences Chromodomain Cell biology 03 medical and health sciences chemistry.chemical_compound chemistry Gene expression PRC1 Gene Psychological repression DNA 030304 developmental biology |
| Zdroj: | SSRN Electronic Journal |
| ISSN: | 1556-5068 |
| DOI: | 10.2139/ssrn.3378003 |
| Popis: | Polycomb-directed repression of gene expression is frequently misregulated in human diseases. A quantitative and target-specific cellular assay was utilized to discover the first potent positive allosteric modulator (PAM), UNC4976, of nucleic acid binding by CBX7, a chromodomain methyl-lysine reader of Polycomb Repressive Complex 1. The PAM activity of UNC4976 resulted in enhanced efficacy across three orthogonal cellular assays by simultaneously antagonizing H3K27me3-specific recruitment of CBX7 to target genes while increasing non-specific binding to DNA and RNA. PAM activity thereby reequilibrates PRC1 away from H3K27me3 target regions. Together, our discovery and characterization of UNC4976 not only revealed the most cellularly potent PRC1-specific chemical probe to date, but also uncovers a potential mechanism of Polycomb regulation with implications for non-histone lysine methylated interaction partners. |
| Databáze: | OpenAIRE |
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