Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.
Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.
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DOI：
10.1038/ncomms11316
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发表时间：
2016-04-28
影响因子：
16.6
通讯作者：
Gamblin SJ
中科院分区：
文献类型：
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作者：
Justin N;Zhang Y;Tarricone C;Martin SR;Chen S;Underwood E;De Marco V;Haire LF;Walker PA;Reinberg D;Wilson JR;Gamblin SJ
Polycomb suppression complex 2 （PRC2）通过其催化SET结构域使组蛋白H3 （H3K27me3）的K27三甲基化，从而沉默基因表达。PRC2底物组蛋白H3K27M的错义突变与某些儿童脑癌有关，并与受影响细胞中H3K27me3的整体减少有关，这种减少被认为是通过抑制PRC2活性来介导的。我们在这里展示了人类PRC2的晶体结构，它与抑制H3K27M肽结合在SET结构域的活性位点上，蛋氨酸残基位于通常容纳目标赖氨酸残基的口袋中。结构和结合研究提示了H3K27M的抑癌机制。该结构还揭示了抑制标记（如H3K27me3）与复合物的EED亚基的结合如何导致SET结构域的催化效率增强，从而导致这种抑制性组蛋白修饰的传播。Polycomb suppression complex 2 （PRC2）通过组蛋白H3 （H3K27Me）的K27三甲基化来沉默基因表达。在这里，作者报告了人类PRC2复合物与致癌性H3K27M突变体结合的结构，并提出了其在儿童脑癌中的效力机制。
Polycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27me3) via its catalytic SET domain. A missense mutation in the substrate of PRC2, histone H3K27M, is associated with certain pediatric brain cancers and is linked to a global decrease of H3K27me3 in the affected cells thought to be mediated by inhibition of PRC2 activity. We present here the crystal structure of human PRC2 in complex with the inhibitory H3K27M peptide bound to the active site of the SET domain, with the methionine residue located in the pocket that normally accommodates the target lysine residue. The structure and binding studies suggest a mechanism for the oncogenic inhibition of H3K27M. The structure also reveals how binding of repressive marks, like H3K27me3, to the EED subunit of the complex leads to enhancement of the catalytic efficiency of the SET domain and thus the propagation of this repressive histone modification. Polycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27Me). Here, the authors report the structure of the human PRC2 complex bound to the oncogenic H3K27M mutant, and suggest a mechanism for its potency in childhood brain cancers.