S-adenosyl-methionine-dependent DNA methyltransferase and histone methyltransferase (SAM-dependent DNMT and HMT)

S-adenosyl-methionine-dependent DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs) are essential epigenetic enzymes that utilize S-adenosyl-methionine (SAM) as a universal methyl donor to modify DNA and histone proteins [1, 3]. DNMTs, including DNMT1, DNMT3A, and DNMT3B, catalyze the methylation of cytosine bases, a process vital for gene silencing, X-chromosome inactivation, and genomic imprinting [1, 4]. HMTs, such as EZH2 and DOT1L, target specific lysine or arginine residues on histones to modulate chromatin architecture and gene expression [1, 3]. In many diseases, particularly cancer, these enzymes are frequently mutated or overexpressed, leading to the epigenetic silencing of tumor suppressor genes or the promotion of oncogenic programs [3, 4]. Pharmacological targeting of these enzymes has led to the development of DNA-hypomethylating agents like azacitidine and selective HMT inhibitors like tazemetostat [2]. These drugs aim to restore normal gene expression patterns, though they are often associated with side effects such as myelosuppression due to their broad impact on cellular regulation [2, 4].

Other names

SAM-dependent methyltransferasesDNA methyltransferasesHistone methyltransferasesProtein methyltransferasesEpigenetic methyltransferases

Inhibition of methyltransferase activity through DNA incorporation (nucleoside analogs) or competitive binding at the S-adenosyl-methionine (SAM) pocket, leading to DNA hypomethylation or altered histone methylation patterns.