Mulholland Christopher B, Nishiyama Atsuya
Faculty of Biology and Center for Molecular Biosystems (BioSysM), Human Biology and BioImaging, Ludwig-Maximilians-Universität München.
Department of Cancer Cell Biology, Institute of Medical Science, The University of Tokyo.
Genes Genet Syst. 2025 Sep 12;100. doi: 10.1266/ggs.25-00073. Epub 2025 Jul 11.
Maintenance DNA methylation is essential for the stable inheritance of epigenetic information in vertebrates. While DNMT1 has long been recognized as the principal maintenance methyltransferase, recent studies have shown that its activity critically depends on ubiquitin signaling. Specifically, the E3 ligase UHRF1 enables DNMT1 recruitment and activation at hemimethylated sites through dual monoubiquitylation of both replication-associated and histone substrates. These insights have revised classical models of maintenance methylation and revealed new layers of regulation involving chromatin context, histone modifications and nucleosome remodeling. In this review, we summarize the current understanding of the molecular mechanisms underlying DNMT1-mediated maintenance methylation, with a particular focus on ubiquitin-dependent pathways and their interplay with chromatin architecture.
维持性DNA甲基化对于脊椎动物表观遗传信息的稳定遗传至关重要。虽然长期以来DNMT1一直被认为是主要的维持性甲基转移酶，但最近的研究表明，其活性关键取决于泛素信号传导。具体而言，E3连接酶UHRF1通过对复制相关底物和组蛋白底物进行双单泛素化，使DNMT1在半甲基化位点募集并激活。这些见解修正了维持性甲基化的经典模型，并揭示了涉及染色质背景、组蛋白修饰和核小体重塑的新调控层面。在本综述中，我们总结了目前对DNMT1介导的维持性甲基化潜在分子机制的理解，特别关注泛素依赖性途径及其与染色质结构的相互作用。
