Polycomb-repressive complex 2 (PRC2) is a histone methyltransferase that is critical for regulating transcriptional repression in mammals. Its catalytic subunit, EZH2, is responsible for the trimethylation of H3K27 and also undergoes automethylation. Using mass spectrometry analysis of recombinant human PRC2, we identified three methylated lysine residues (K510, K514, and K515) on a disordered but highly conserved loop of EZH2. Methylation of these lysines increases PRC2 histone methyltransferase activity, whereas their mutation decreases activity in vitro. De novo histone methylation in an EZH2 knockout cell line is greatly impeded by mutation of the automethylation lysines. EZH2 automethylation occurs intramolecularly (in cis) by methylation of a pseudosubstrate sequence on a flexible loop. This posttranslational modification and cis regulation of PRC2 are analogous to the activation of many protein kinases by autophosphorylation. We propose that EZH2 automethylation allows PRC2 to modulate its histone methyltransferase activity by sensing histone H3 tails, SAM concentration, and perhaps other effectors.

中文翻译：

---

通过PRC2的自动甲基化调节组蛋白甲基化。

多梳抑制复合物 2 (PRC2) 是一种组蛋白甲基转移酶，对调节哺乳动物的转录抑制至关重要。它的催化亚基 EZH2 负责 H3K27 的三甲基化，并且也经历自动甲基化。使用重组人 PRC2 的质谱分析，我们在 EZH2 的无序但高度保守的环上鉴定了三个甲基化赖氨酸残基（K510、K514 和 K515）。这些赖氨酸的甲基化增加了PRC2组蛋白甲基转移酶的活性，而它们的突变降低了体外的活性。EZH2 敲除细胞系中的从头组蛋白甲基化受到自甲基化赖氨酸突变的极大阻碍。EZH2 自动甲基化通过柔性环上的假底物序列的甲基化在分子内（顺式）发生。PRC2 的这种翻译后修饰和顺式调节类似于通过自磷酸化激活许多蛋白激酶。我们建议 EZH2 自动甲基化允许 PRC2 通过感知组蛋白 H3 尾部、SAM 浓度和可能的其他效应器来调节其组蛋白甲基转移酶活性。