The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states
The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states
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DOI：
10.1016/j.febslet.2011.08.018
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发表时间：
2011-10-03
期刊：
影响因子：
3.5
通讯作者：
Scott, Margaret Porter
中科院分区：
文献类型：
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作者：
Wigle, Tim J.;Knutson, Sarah K.;Scott, Margaret Porter
已在非霍奇金淋巴瘤 (NHL) 某些亚型患者中发现了 EZH2 SET 结构域中酪氨酸 641（Y641F、Y641N、Y641S 和 Y641H）的突变。这些突变显示出改变 EZH2 对组蛋白 H3 (H3K27) 上赖氨酸 27 的各种甲基化状态的底物特异性。在一名 NHL 患者和一名骨髓增生异常综合征 (MDS) 患者的 SKM-1 细胞中还发现了 EZH2 Y641 突变为半胱氨酸 (Y641C)。据报道，Y641C 突变会显着降低酶活性。在这里，我们证明，虽然 Y641C 突变消除了针对非甲基化和单甲基化 H3K27 的酶活性，但它在催化二甲基化前体形成三甲基化 H3K27 方面优于野生型。 (C) 2011 年欧洲生化学会联合会。由 Elsevier B.V. 出版。保留所有权利。
Mutations at tyrosine 641 (Y641F, Y641N, Y641S and Y641H) in the SET domain of EZH2 have been identified in patients with certain subtypes of non-Hodgkin lymphoma (NHL). These mutations were shown to change the substrate specificity of EZH2 for various methylation states of lysine 27 on histone H3 (H3K27). An additional mutation at EZH2 Y641 to cysteine (Y641C) was also found in one patient with NHL and in SKM-1 cells derived from a patient with myelodisplastic syndrome (MDS). The Y641C mutation has been reported to dramatically reduce enzymatic activity. Here, we demonstrate that while the Y641C mutation ablates enzymatic activity against unmethylated and monomethylated H3K27, it is superior to wild-type in catalyzing the formation of trimethylated H3K27 from the dimethylated precursor. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.