The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate.
The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate.
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DOI：
10.1074/jbc.m109.034462
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发表时间：
2009-12-04
期刊：
影响因子：
--
通讯作者：
Reinberg D
中科院分区：
文献类型：
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作者：
Li Y;Trojer P;Xu CF;Cheung P;Kuo A;Drury WJ 3rd;Qiao Q;Neubert TA;Xu RM;Gozani O;Reinberg D
组蛋白赖氨酸甲基转移酶NSD家族是染色质完整性的重要参与者，与其家族成员的异常表达相关的人类疾病的数量证明了这一点。然而，这些酶的具体靶点并不清楚，文献中报道了明显的差异。我们证明，基于所提供底物的性质，NSD2可以表现出不同的靶向偏好。从人细胞中纯化的NSD2复合体和重组NSD2在提供核小体底物时都显示出对组蛋白H3赖氨酸36(H3K36)的特异性靶向，但在八聚体底物的情况下，组蛋白H4赖氨酸44是主要靶点，无论组蛋白是天然的还是重组的。当NSD2与八聚体靶标结合短的单链或双链DNA时，这种差异就被抵消了。虽然八聚体不能形成核小体，但目标是核小体特异的，就像产物二甲基化H3K36一样。这项研究在一定程度上澄清了以前报告的关于NSD目标的差异。我们认为DNA作为NSD2的变构效应使H3K36成为首选靶点。
The NSD (nuclear receptor SET domain-containing) family of histone lysine methyltransferases is a critical participant in chromatin integrity as evidenced by the number of human diseases associated with the aberrant expression of its family members. Yet, the specific targets of these enzymes are not clear, with marked discrepancies being reported in the literature. We demonstrate that NSD2 can exhibit disparate target preferences based on the nature of the substrate provided. The NSD2 complex purified from human cells and recombinant NSD2 both exhibit specific targeting of histone H3 lysine 36 (H3K36) when provided with nucleosome substrates, but histone H4 lysine 44 is the primary target in the case of octamer substrates, irrespective of the histones being native or recombinant. This disparity is negated when NSD2 is presented with octamer targets in conjunction with short single- or double-stranded DNA. Although the octamers cannot form nucleosomes, the target is nonetheless nucleosome-specific as is the product, dimethylated H3K36. This study clarifies in part the previous discrepancies reported with respect to NSD targets. We propose that DNA acts as an allosteric effector of NSD2 such that H3K36 becomes the preferred target.