Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Science. 2011 Feb 25;331(6020):1036-40. doi: 10.1126/science.1195380. Epub 2010 Dec 16.
Maintenance of genomic methylation patterns is mediated primarily by DNA methyltransferase-1 (DNMT1). We have solved structures of mouse and human DNMT1 composed of CXXC, tandem bromo-adjacent homology (BAH1/2), and methyltransferase domains bound to DNA-containing unmethylated CpG sites. The CXXC specifically binds to unmethylated CpG dinucleotide and positions the CXXC-BAH1 linker between the DNA and the active site of DNMT1, preventing de novo methylation. In addition, a loop projecting from BAH2 interacts with the target recognition domain (TRD) of the methyltransferase, stabilizing the TRD in a retracted position and preventing it from inserting into the DNA major groove. Our studies identify an autoinhibitory mechanism, in which unmethylated CpG dinucleotides are occluded from the active site to ensure that only hemimethylated CpG dinucleotides undergo methylation.
基因组甲基化模式的维持主要是由 DNA 甲基转移酶-1（DNMT1）介导的。我们已经解决了由CXXC、串联溴相邻同源（BAH1/2）和甲基转移酶结构域组成的小鼠和人 DNMT1 的结构，这些结构与含有未甲基化 CpG 位点的 DNA 结合。CXXC 特异性结合未甲基化的 CpG 二核苷酸，并将 CXXC-BAH1 接头定位于 DNA 和 DNMT1 的活性位点之间，从而防止从头甲基化。此外，从 BAH2 伸出的一个环与甲基转移酶的靶识别结构域（TRD）相互作用，将 TRD 稳定在缩回位置，防止其插入 DNA 大沟。我们的研究确定了一种自动抑制机制，其中未甲基化的 CpG 二核苷酸被排除在活性位点之外，以确保仅半甲基化的 CpG 二核苷酸发生甲基化。
