Enhanced processivity of Dnmt1 by monoubiquitinated histone H3
Enhanced processivity of Dnmt1 by monoubiquitinated histone H3
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DOI：
10.1111/gtc.12732
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发表时间：
2019-12-03
期刊：
影响因子：
2.1
通讯作者：
Suetake, Isao
中科院分区：
文献类型：
--
作者：
Mishima, Yuichi;Brueckner, Laura;Suetake, Isao
DNA甲基化控制基因表达，一旦建立，DNA甲基化模式在DNA复制期间通过维持DNA甲基转移酶Dnmt 1忠实地复制。在体内，Dnmt 1与识别半甲基化CpG的Uhrf 1相互作用。最近，我们报道了Uhrf 1催化的K18-和K23-泛素化组蛋白H3与Dnmt 1的N-末端区域（复制焦点靶向序列，RFTS）结合以刺激其甲基转移酶活性。然而，目前还没有完全了解泛素化组蛋白H3如何刺激Dnmt 1活性。在这里，我们发现，monoubiquitinated组蛋白H3刺激Dnmt 1对DNA的活性与多个半甲基化的CpG，但不对DNA只有一个半甲基化的CpG，这表明泛素化的影响Dnmt 1的持续合成能力。单泛素化组蛋白H3刺激的Dnmt 1活性被Uhrf 1 SRA结构域（也与RFTS结合）相加增强。因此，Dnmt 1活性受到Uhrf 1催化（遍在蛋白化）依赖性和非依赖性功能的调节。
DNA methylation controls gene expression, and once established, DNA methylation patterns are faithfully copied during DNA replication by the maintenance DNA methyltransferase Dnmt1. In vivo, Dnmt1 interacts with Uhrf1, which recognizes hemimethylated CpGs. Recently, we reported that Uhrf1-catalyzed K18- and K23-ubiquitinated histone H3 binds to the N-terminal region (the replication focus targeting sequence, RFTS) of Dnmt1 to stimulate its methyltransferase activity. However, it is not yet fully understood how ubiquitinated histone H3 stimulates Dnmt1 activity. Here, we show that monoubiquitinated histone H3 stimulates Dnmt1 activity toward DNA with multiple hemimethylated CpGs but not toward DNA with only a single hemimethylated CpG, suggesting an influence of ubiquitination on the processivity of Dnmt1. The Dnmt1 activity stimulated by monoubiquitinated histone H3 was additively enhanced by the Uhrf1 SRA domain, which also binds to RFTS. Thus, Dnmt1 activity is regulated by catalysis (ubiquitination)-dependent and -independent functions of Uhrf1.