Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria; Department of Biochemistry and Molecular Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Cell Chem Biol. 2019 Oct 17;26(10):1365-1379.e22. doi: 10.1016/j.chembiol.2019.07.013. Epub 2019 Aug 15.
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) peptidomimetic, 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.
多梳抑制基因表达在人类疾病中经常失调。本研究采用一种定量且靶向特异性的细胞测定方法，发现了第一个强效的核酸结合的 CBX7 正别构调节剂（PAM）肽模拟物 UNC4976，CBX7 是多梳抑制复合物 1 的一个染色质域甲基赖氨酸读取器。UNC4976 的 PAM 活性通过同时拮抗 H3K27me3 特异性募集 CBX7 到靶基因，同时增加与 DNA 和 RNA 的非特异性结合，从而增强了三种正交细胞测定中的功效。PAM 活性因此使 PRC1 从 H3K27me3 靶区域重新平衡。总之，我们对 UNC4976 的发现和表征不仅揭示了迄今为止最具细胞活性的 PRC1 特异性化学探针，而且还揭示了多梳调控的潜在机制，这对非组蛋白赖氨酸甲基化相互作用伙伴具有重要意义。
