组蛋白甲基化酶EZH2的非经典作用

Noncanonical role of histone methylase EZH2

Zeste同源物增强子2(enhancer of zeste homolog 2,EZH2)、胚胎外胚层发育蛋白(embryonic ectoderm development,EED)和zeste12同源蛋白抑制子(suppressor of zeste 12,SUZ12)是Polycomb蛋白家族PRC2复合体的核心元件。EZH2的经典作用为以PRC2复合体依赖的方式诱导组蛋白H3在K27位甲基化,从而引起基因沉默,参与调控细胞增殖、分化、衰老及肿瘤发生。本文介绍了EZH2的一些非经典功能,简述了EZH2作为一个多功能分子,不仅通过PRC2复合体依赖与非依赖的方式甲基化修饰一系列非组蛋白分子,影响其功能调节;还可与转录因子及辅因子直接相互作用,作为支架分子参与转录复合物组装,发挥转录抑制或转录激活作用。此外,EZH2还具有不依赖于转录的其他功能,如调控细胞迁移、信号通路活化、DNA复制和损伤修复、与RNA结合等。EZH2在经典和非经典作用之间的转换,与不同激酶和信号通路的调控有关。本文提示EZH2在生命活动中具有重要作用,其在不同生物学事件和疾病中的效应和调控方式有待进一步深入研究。

The polycomb repressive complex 2(PRC2)is composed of EZH2,EED and SUZ12.EZH2 is a highly conserved histone methyltransferase that catalyzes trimethylation of histone H3 lysine 27(H3 K27 me3)for repressing target gene expression.The canonical role of EZH2 is gene silencing through methylating lysine27 of histone H3 in a PRC2-dependent manner.In this way,EZH2 participates in the regulation of cell proliferation,apoptosis,senescence and tumorigenesis.Recent studies indicate that EZH2 is a pleiotropic molecule beyond a histone methytransferase.Firstly,EZH2 can methylate and modulate a variety of nonhistone proteins in PRC2-dependent or PRC2-independent fashion.Secondly,EZH2 also forms physical interactions with a subset of transcriptional factors and transcriptional coactivators to context-dependently influence gene expression.Meanwhile,noncanonical roles of EZH2 also include the regulation of cell migration,signaling activation,DNA repair,DNA replication,as well as interaction with RNA.The switch of EZH2 between its canonical and noncanonical activities is dynamically regulated by different kinases and signaling pathways.Obviously,the complexity of EZH2 implicates its importance in various cellular events.It is necessary to understand the functional regulation and biological effects of EZH2 in defined cellular events and diseases.