Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain
Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain
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DOI：
10.1038/embor.2009.218
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发表时间：
2009-11-01
期刊：
影响因子：
7.7
通讯作者：
Shirakawa, Masahiro
中科院分区：
文献类型：
--
作者：
Otani, Junji;Nankumo, Toshiyuki;Shirakawa, Masahiro
DNMT3蛋白是一种从头DNA甲基转移酶，负责在哺乳动物基因组中建立DNA甲基化模式。在这里，我们确定了DNMT3A的ATRX-DNMT3-DNMT3L(ADD)结构域的晶体结构。结合生化分析的结果，DNMT3A的复杂结构表明DNMT3A识别组蛋白H3中赖氨酸4的未甲基化状态。这一发现表明，DNMT3A在染色质上的募集，从而从头开始DNA甲基化，是由其ADD结构域对组蛋白修饰状态的识别所介导的。此外，我们的生化和核磁共振数据表明，DNMT3A的添加结构域和异染色质蛋白1α的染色域相互排斥地结合到H3尾部。这些结果表明，DNMT3A的从头DNA甲基化需要改变染色质的结构。
DNMT3 proteins are de novo DNA methyltransferases that are responsible for the establishment of DNA methylation patterns in mammalian genomes. Here, we have determined the crystal structures of the ATRX-DNMT3-DNMT3L (ADD) domain of DNMT3A in an unliganded form and in a complex with the amino-terminal tail of histone H3. Combined with the results of biochemical analysis, the complex structure indicates that DNMT3A recognizes the unmethylated state of lysine 4 in histone H3. This finding indicates that the recruitment of DNMT3A onto chromatin, and thereby de novo DNA methylation, is mediated by recognition of the histone modification state by its ADD domain. Furthermore, our biochemical and nuclear magnetic resonance data show mutually exclusive binding of the ADD domain of DNMT3A and the chromodomain of heterochromatin protein 1 alpha to the H3 tail. These results indicate that de novo DNA methylation by DNMT3A requires the alteration of chromatin structure.