The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA
The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA
复制标题
DOI：
10.1038/nature06397
复制
发表时间：
2007-12-06
期刊：
影响因子：
64.8
通讯作者：
Koseki, Haruhiko
中科院分区：
文献类型：
--
作者：
Sharif, Jafar;Muto, Masahiro;Koseki, Haruhiko
DNA甲基转移酶（胞嘧啶-5）1 （Dnmt1）是维持CpG甲基化的主要酶，对基因表达、寄生DNA元件沉默、基因组印迹和胚胎发生的调控至关重要（1-4）。在S期需要Dnmt1来甲基化在DNA母链上发生相反甲基化的新复制的CpGs，这对于基因组甲基化模式的表观遗传至关重要。尽管Dnmt1对这种半甲基化DNA具有内在的亲和力(5)，但确保Dnmt1在体内正确装载到新复制的DNA上的分子机制尚不清楚。Np95（也称为Uhrf1和ICBP90）蛋白通过其SET和RING finger-associated （SRA）结构域结合甲基化的CpG(6)。在这里，我们发现小鼠Np95复制异染色质的定位依赖于半甲基化DNA的存在。Np95与Dnmt1形成复合物，介导Dnmt1装载到复制异染色质区域。通过使用缺乏Np95的胚胎干细胞和胚胎，我们发现Np95对维持体内整体和局部DNA甲基化以及抑制反转录转座子和印迹基因的转录至关重要。因此，半甲基化DNA、Np95和Dnmt1之间的联系建立了DNA甲基化表观遗传机制的关键步骤。
DNA methyltransferase (cytosine-5) 1 (Dnmt1) is the principal enzyme responsible for maintenance of CpG methylation and is essential for the regulation of gene expression, silencing of parasitic DNA elements, genomic imprinting and embryogenesis(1-4). Dnmt1 is needed in S phase to methylate newly replicated CpGs occurring opposite methylated ones on the mother strand of the DNA, which is essential for the epigenetic inheritance of methylation patterns in the genome. Despite an intrinsic affinity of Dnmt1 for such hemi-methylated DNA(5), the molecular mechanisms that ensure the correct loading of Dnmt1 onto newly replicated DNA in vivo are not understood. The Np95 ( also known as Uhrf1 and ICBP90) protein binds methylated CpG through its SET and RING finger-associated ( SRA) domain(6). Here we show that localization of mouse Np95 to replicating heterochromatin is dependent on the presence of hemi-methylated DNA. Np95 forms complexes with Dnmt1 and mediates the loading of Dnmt1 to replicating heterochromatic regions. By using Np95-deficient embryonic stem cells and embryos, we show that Np95 is essential in vivo to maintain global and local DNA methylation and to repress transcription of retrotransposons and imprinted genes. The link between hemimethylated DNA, Np95 and Dnmt1 thus establishes key steps of the mechanism for epigenetic inheritance of DNA methylation.