Department of Genetics, Dartmouth Medical School, USA.
Brief Funct Genomics. 2012 May;11(3):217-26. doi: 10.1093/bfgp/els017. Epub 2012 May 30.
Methylation of histone H3 at lysine 4 (H3K4) is a conserved feature of active chromatin catalyzed by methyltransferases of the SET1-family (SET1A, SET1B, MLL1, MLL2, MLL3 and MLL4 in humans). These enzymes participate in diverse gene regulatory networks with a multitude of known biological functions, including direct involvement in several human disease states. Unlike most lysine methyltransferases, SET1-family enzymes are only fully active in the context of a multi-subunit complex, which includes a protein module comprised of WDR5, RbBP5, ASH2L and DPY-30 (WRAD). These proteins bind in close proximity to the catalytic SET domain of SET1-family enzymes and stimulate H3K4 methyltransferase activity. The mechanism by which WRAD promotes catalysis involves elements of allosteric control and possibly the utilization of a second H3K4 methyltransferase active site present within WRAD itself. WRAD components also engage in physical interactions that recruit SET1-family proteins to target sites on chromatin. Here, the known molecular mechanisms through which WRAD enables the function of SET1-related enzymes will be reviewed.
组蛋白 H3 赖氨酸 4 位的甲基化（H3K4）是活性染色质的保守特征，由 SET1 家族的甲基转移酶（人源中的 SET1A、SET1B、MLL1、MLL2、MLL3 和 MLL4）催化。这些酶参与多种基因调控网络，具有多种已知的生物学功能，包括直接参与多种人类疾病状态。与大多数赖氨酸甲基转移酶不同，SET1 家族的酶仅在多亚基复合物的背景下才具有完全活性，该复合物包括由 WDR5、RbBP5、ASH2L 和 DPY-30（WRAD）组成的蛋白质模块。这些蛋白质与 SET1 家族酶的催化 SET 结构域紧密结合，并刺激 H3K4 甲基转移酶活性。WRAD 促进催化的机制涉及变构控制的要素，并且可能利用存在于 WRAD 自身内的第二个 H3K4 甲基转移酶活性位点。WRAD 组件还进行物理相互作用，将 SET1 家族蛋白募集到染色质上的靶位点。在这里，将回顾 WRAD 使 SET1 相关酶发挥功能的已知分子机制。
