漆酚 A 是一种直接的、与 DNA 竞争的 DNA 甲基转移酶 1 抑制剂。
Laccaic acid A is a direct, DNA-competitive inhibitor of DNA methyltransferase 1.
机构信息
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
出版信息
J Biol Chem. 2013 Aug 16;288(33):23858-67. doi: 10.1074/jbc.M113.480517. Epub 2013 Jul 9.
Abstract
Methylation of cytosines in CpG dinucleotides is the predominant epigenetic mark on vertebrate DNA. DNA methylation is associated with transcriptional repression. The pattern of DNA methylation changes during development and with disease. Human DNA methyltransferase 1 (Dnmt1), a 1616-amino acid multidomain enzyme, is essential for maintenance of DNA methylation in proliferating cells and is considered an important cancer drug target. Using a fluorogenic, endonuclease-coupled DNA methylation assay with an activated form of Dnmt1 engineered to lack the replication foci targeting sequence domain, we discovered that laccaic acid A (LCA), a highly substituted anthraquinone natural product, is a direct inhibitor with a 310 nm Ki. LCA is competitive with the DNA substrate in in vitro methylation assays and alters the expression of methylated genes in MCF-7 breast cancer cells synergistically with 5-aza-2'-deoxycytidine. LCA represents a novel class of Dnmt-targeted molecular probes, with biochemical properties that allow it to distinguish between non DNA-bound and DNA-bound Dnmt1.
摘要
胞嘧啶的 CpG 二核苷酸中的甲基化是脊椎动物 DNA 上主要的表观遗传标记。DNA 甲基化与转录抑制有关。DNA 甲基化的模式在发育过程中以及与疾病相关的过程中会发生变化。人类 DNA 甲基转移酶 1（Dnmt1）是一种 1616 个氨基酸的多结构域酶，对于增殖细胞中 DNA 甲基化的维持是必不可少的，被认为是癌症药物的重要靶点。我们使用一种带有活性形式的 Dnmt1 的荧光内切酶偶联 DNA 甲基化测定法，该活性形式的 Dnmt1 缺乏复制焦点靶向序列结构域，发现漆酚 A（LCA）是一种高度取代的蒽醌天然产物，是一种直接抑制剂，Ki 值为 310nm。LCA 在体外甲基化测定中与 DNA 底物竞争，并与 5-氮杂-2'-脱氧胞苷协同改变 MCF-7 乳腺癌细胞中甲基化基因的表达。LCA 代表了一类新型的 Dnmt 靶向分子探针，其生化特性使其能够区分非 DNA 结合和 DNA 结合的 Dnmt1。
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