PDF(Pubmed)
Abstract：
Functional crosstalk between DNA methylation, histone H3 lysine-9 trimethylation (H3K9me3) and heterochromatin protein 1 (HP1) is essential for proper heterochromatin assembly and genome stability. However, how repressive chromatin cues guide DNA methyltransferases for region-specific DNA methylation remains largely unknown. Here, we report structure-function characterizations of DNA methyltransferase Defective-In-Methylation-2 (DIM2) in Neurospora. The DNA methylation activity of DIM2 requires the presence of both H3K9me3 and HP1. Our structural study reveals a bipartite DIM2-HP1 interaction, leading to a disorder-to-order transition of the DIM2 target-recognition domain that is essential for substrate binding. Furthermore, the structure of DIM2-HP1-H3K9me3-DNA complex reveals a substrate-binding mechanism distinct from that for its mammalian orthologue DNMT1. In addition, the dual recognition of H3K9me3 peptide by the DIM2 RFTS and BAH1 domains allosterically impacts the DIM2-substrate binding, thereby controlling DIM2-mediated DNA methylation. Together, this study uncovers how multiple heterochromatin factors coordinately orchestrate an activity-switching mechanism for region-specific DNA methylation.
摘要：
DNA甲基化之间的功能串扰，组蛋白H3赖氨酸-9三甲基化（H3K9me3）和异染色质蛋白1（HP1）对于适当的异染色质组装和基因组稳定性至关重要。然而,抑制性染色质线索如何指导DNA甲基转移酶进行区域特异性DNA甲基化仍在很大程度上未知.这里,我们报道了神经孢菌DNA甲基转移酶在甲基化缺陷-2（DIM2）中的结构-功能特征。DIM2的DNA甲基化活性需要同时存在H3K9me3和HP1。我们的结构研究揭示了二分DIM2-HP1相互作用，导致对底物结合至关重要的DIM2靶识别域的无序转换。此外，DIM2-HP1-H3K9me3-DNA复合物的结构揭示了与其哺乳动物直向同源物DNMT1不同的底物结合机制。此外,DIM2RFTS和BAH1结构域对H3K9me3肽的双重识别变构地影响DIM2-底物结合，从而控制DIM2介导的DNA甲基化。一起,这项研究揭示了多种异染色质因子如何协调区域特异性DNA甲基化的活性转换机制.
