Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, India.
Epigenetics. 2012 Sep;7(9):994-1007. doi: 10.4161/epi.21568. Epub 2012 Aug 16.
DNA methylation is one of the principal epigenetic signals that participate in cell specific gene expression in vertebrates. DNA methylation plays a quintessential role in the control of gene expression, cellular differentiation and development. It also plays a central role in the preservation of chromatin structure and chromosomal integrity, parental imprinting, X-chromosome inactivation, aging and carcinogenesis. The foremost contributor in the mammalian methylation scheme is DNMT1, a maintenance methyltransferase that faithfully copies the pre-existing methyl marks onto hemimethylated daughter strands during DNA replication to maintain the established methylation patterns across successive cell divisions. The ever-changing cellular physiology and the significant part that DNA methylation plays in genome regulation necessitate rigid management of this enzyme. In mammalian cells, a host of intrinsic and extrinsic mechanisms regulate the expression, activity and stability of DNMT1. Transcriptional regulation, post-transcriptional auto-inhibitory controls and post-translational modifications of the enzyme are responsible for the efficient inheritance of DNA methylation patterns. Also, a large number of intra- and intercellular signaling cascades and numerous interactions with other modulator molecules that affect the catalytic activity of the enzyme at multiple levels function as major checkpoints of the DNMT1 control system. An in-depth understanding of the DNMT1 enzyme, its targeting and function is crucial for comprehending how DNA methylation is coordinated with other critical developmental and physiological processes. This review aims to provide a comprehensive account of the various regulatory mechanisms and interactions of DNMT1 so as to elucidate its function at the molecular level and understand the dynamics of DNA methylation at the cellular level.
DNA 甲基化是脊椎动物中参与细胞特异性基因表达的主要表观遗传信号之一。DNA 甲基化在基因表达、细胞分化和发育的控制中起着至关重要的作用。它在维持染色质结构和染色体完整性、亲本印迹、X 染色体失活、衰老和癌变中也起着核心作用。哺乳动物甲基化方案的主要贡献者是 DNMT1，它是一种维持甲基转移酶，在 DNA 复制过程中忠实地将预先存在的甲基标记复制到半甲基化的子链上，以在随后的细胞分裂中维持已建立的甲基化模式。不断变化的细胞生理学和 DNA 甲基化在基因组调控中所起的重要作用需要对这种酶进行严格的管理。在哺乳动物细胞中，许多内在和外在的机制调节 DNMT1 的表达、活性和稳定性。转录调控、转录后自动抑制控制和酶的翻译后修饰负责有效地遗传 DNA 甲基化模式。此外，大量的细胞内和细胞间信号级联以及与其他调节剂分子的许多相互作用，以多种水平影响酶的催化活性，作为 DNMT1 控制系统的主要检查点。深入了解 DNMT1 酶及其靶向和功能对于理解 DNA 甲基化如何与其他关键发育和生理过程协调至关重要。本综述旨在全面描述 DNMT1 的各种调节机制和相互作用，以阐明其在分子水平上的功能，并理解细胞水平上 DNA 甲基化的动态。
