Kikuchi Amika, Arita Kyohei
Structural Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University.
Genes Genet Syst. 2025 Sep 12;100. doi: 10.1266/ggs.25-00051. Epub 2025 Jun 5.
DNA methylation is faithfully inherited during cell division, playing a crucial role in maintaining cellular identity. The process of DNA methylation maintenance relies on the DNA methyltransferase DNMT1 and the ubiquitin E3 ligase UHRF1. UHRF1 facilitates the ubiquitination of both the replication factor PAF15 and histone H3, with each ubiquitin signal regulating replication-coupled and -uncoupled DNA methylation maintenance, respectively. Over the past decades, advances in structural biology have significantly deepened our understanding of the molecular mechanisms governing DNA methylation maintenance. In particular, the emergence of cryo-electron microscopy-often referred to as the "resolution revolution"-has transformed many areas of biology, including epigenetics and chromatin biology. This review focuses on the structural mechanisms of DNA methylation maintenance, as revealed by the three-dimensional structures of key biomolecular complexes, and discusses the potential development of inhibitors targeting DNA methylation maintenance factors based on structural insights.
DNA甲基化在细胞分裂过程中被忠实地遗传，在维持细胞特性方面发挥着关键作用。DNA甲基化维持过程依赖于DNA甲基转移酶DNMT1和泛素E3连接酶UHRF1。UHRF1促进复制因子PAF15和组蛋白H3的泛素化，每个泛素信号分别调节复制偶联和非偶联的DNA甲基化维持。在过去几十年中，结构生物学的进展显著加深了我们对DNA甲基化维持分子机制的理解。特别是，冷冻电子显微镜的出现——常被称为“分辨率革命”——已经改变了生物学的许多领域，包括表观遗传学和染色质生物学。本综述重点关注关键生物分子复合物的三维结构所揭示的DNA甲基化维持的结构机制，并基于结构见解讨论靶向DNA甲基化维持因子的抑制剂的潜在发展。
