Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560 064, India.
J Biol Chem. 2010 Mar 5;285(10):7143-52. doi: 10.1074/jbc.M109.063933. Epub 2009 Dec 17.
Methylation of the arginine residues of histones by methyltransferases has important consequences for chromatin structure and gene regulation; however, the molecular mechanism(s) of methyltransferase regulation is still unclear, as is the biological significance of methylation at particular arginine residues. Here, we report a novel specific inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1; also known as PRMT4) that selectively inhibits methylation at arginine 17 of histone H3 (H3R17). Remarkably, this plant-derived inhibitor, called TBBD (ellagic acid), binds to the substrate (histone) preferentially at the signature motif, "KAPRK," where the proline residue (Pro-16) plays a critical role for interaction and subsequent enzyme inhibition. In a promoter-specific context, inhibition of H3R17 methylation represses expression of p21, a p53-responsive gene, thus implicating a possible role for H3 Arg-17 methylation in tumor suppressor function. These data establish TBBD as a novel specific inhibitor of arginine methylation and demonstrate substrate sequence-directed inhibition of enzyme activity by a small molecule and its physiological consequence.
组蛋白精氨酸残基的甲基化由甲基转移酶完成，这对染色质结构和基因调控有重要影响；然而，甲基转移酶调控的分子机制尚不清楚，特定精氨酸残基甲基化的生物学意义也不清楚。在这里，我们报告了一种新型的共激活因子相关精氨酸甲基转移酶 1（CARM1；也称为 PRMT4）的特异性抑制剂，它选择性地抑制组蛋白 H3 精氨酸 17 的甲基化（H3R17）。值得注意的是，这种来源于植物的抑制剂称为 TBBD（鞣花酸），它优先在特征基序“KAPRK”处与底物（组蛋白）结合，脯氨酸残基（Pro-16）在相互作用和随后的酶抑制中起着关键作用。在启动子特异性背景下，H3R17 甲基化的抑制抑制了 p21 的表达，p21 是 p53 反应基因，这表明 H3 Arg-17 甲基化可能在肿瘤抑制功能中起作用。这些数据确立了 TBBD 作为精氨酸甲基化的新型特异性抑制剂，并证明了小分子的底物序列导向抑制酶活性及其生理后果。
