Ren Wendan, Gao Linfeng, Song Jikui
Department of Biochemistry, University of California, Riverside, CA 92521, USA.
Environmental Toxicology Program, University of California, Riverside, CA 92521, USA.
Genes (Basel). 2018 Dec 11;9(12):620. doi: 10.3390/genes9120620.
DNA methylation, one of the major epigenetic mechanisms, plays critical roles in regulating gene expression, genomic stability and cell lineage commitment. The establishment and maintenance of DNA methylation in mammals is achieved by two groups of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B, which are responsible for installing DNA methylation patterns during gametogenesis and early embryogenesis, and DNMT1, which is essential for propagating DNA methylation patterns during replication. Both groups of DNMTs are multi-domain proteins, containing a large N-terminal regulatory region in addition to the C-terminal methyltransferase domain. Recent structure-function investigations of the individual domains or large fragments of DNMT1 and DNMT3A have revealed the molecular basis for their substrate recognition and specificity, intramolecular domain-domain interactions, as well as their crosstalk with other epigenetic mechanisms. These studies highlight a multifaceted regulation for both DNMT1 and DNMT3A/3B, which is essential for the precise establishment and maintenance of lineage-specific DNA methylation patterns in cells. This review summarizes current understanding of the structure and mechanism of DNMT1 and DNMT3A-mediated DNA methylation, with emphasis on the functional cooperation between the methyltransferase and regulatory domains.
DNA甲基化是主要的表观遗传机制之一，在调节基因表达、基因组稳定性和细胞谱系定向中发挥关键作用。哺乳动物中DNA甲基化的建立和维持由两组DNA甲基转移酶（DNMT）完成：DNMT3A和DNMT3B，它们负责在配子发生和早期胚胎发生过程中建立DNA甲基化模式；以及DNMT1，它对于在复制过程中传播DNA甲基化模式至关重要。这两组DNMT都是多结构域蛋白，除了C末端甲基转移酶结构域外，还包含一个大的N末端调节区域。最近对DNMT1和DNMT3A的单个结构域或大片段进行的结构-功能研究揭示了它们底物识别和特异性、分子内结构域-结构域相互作用以及它们与其他表观遗传机制相互作用的分子基础。这些研究突出了对DNMT1和DNMT3A/3B的多方面调节，这对于细胞中谱系特异性DNA甲基化模式的精确建立和维持至关重要。本综述总结了目前对DNMT1和DNMT3A介导的DNA甲基化的结构和机制的理解，重点是甲基转移酶和调节结构域之间的功能协作。
