DNAmethyltransferaseinhibitors

DNA methyltransferases (DNMTs) are enzymes that catalyze the transfer of a methyl group from S-adenosyl methionine (SAM) to cytosine bases in genomic DNA, generating 5-methylcytosine. In humans, the DNMT family includes DNMT1, DNMT3A, DNMT3B, and the regulatory factor DNMT3L. DNMT1 is primarily a maintenance methyltransferase that copies methylation patterns to the daughter strand during DNA replication, whereas DNMT3A and DNMT3B are de novo methyltransferases that establish new methylation marks during development. DNMT3L, although catalytically inactive, stimulates DNMT3A and DNMT3B and helps recruit them to chromatin. Methylation most commonly occurs at CpG dinucleotides, though non-CpG methylation is observed in certain cell types and organisms.

Mechanistically, DNMTs require SAM as the methyl donor and operate through a conserved catalytic cycle that forms a covalent enzyme–cytosine intermediate before completing transfer to the 5-position of cytosine. DNMT1 is recruited to hemi-methylated DNA by the UHRF1 protein, linking maintenance methylation to DNA replication. DNMT3A and DNMT3B are guided by chromatin context and histone marks to establish methylation patterns de novo, contributing to cell-type–specific epigenetic landscapes.

Functions and significance include regulation of gene expression, maintenance of genomic imprinting, X-chromosome inactivation, and suppression of transposable elements. DNMT activity shapes developmental processes and is a mechanism by which epigenetic information is inherited across cell divisions. Aberrant DNMT function or methylation patterns are associated with development disorders and cancer, where promoter hypermethylation can silence tumor suppressor genes and global methylation changes can affect genomic stability. DNMT inhibitors are used therapeutically in some hematologic diseases and are active areas of epigenetic research.