Molecular and Enzymatic Profiles of Mammalian DNA Methyltransferases: Structures and Targets for Drugs

Abstract

DNA methylation is an epigenetic event involved in a variety array of processes that may be the foundation of genetic phenomena and diseases. DNA methyltransferase is a key enzyme for cytosine methylation in DNA, and can be divided into two functional families (Dnmt1 and Dnmt3) in mammals. All mammalian DNA methyltransferases are encoded by their own single gene, and consisted of catalytic and regulatory regions (except Dnmt2). Via interactions between functional domains in the regulatory or catalytic regions and other adaptors or cofactors, DNA methyltransferases can be localized at selective areas (specific DNA/nucleotide sequence) and linked to specific chromosome status (euchromatin/heterochromatin, various histone modification status). With assistance from UHRF1 and Dnmt3L or other factors in Dnmt1 and Dnmt3a/ Dnmt3b, mammalian DNA methyltransferases can be recruited, and then specifically bind to hemimethylated and unmethylated double-stranded DNA sequence to maintain and de novo setup patterns for DNA methylation. Complicated enzymatic steps catalyzed by DNA methyltransferases include methyl group transferred from cofactor Ado-Met to C5 position of the flipped-out cytosine in targeted DNA duplex. In the light of the fact that different DNA methyltransferases are divergent in both structures and functions, and use unique reprogrammed or distorted routines in development of diseases, design of new drugs targeting specific mammalian DNA methyltransferases or their adaptors in the control of key steps in either maintenance or de novo DNA methylation processes will contribute to individually treating diseases related to DNA methyltransferases.

Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG)

“…[8][9][10][11][12][13][14][15][16] DNMT3A is located in chromosomal band 2p23 and, together with DNMT3B and DNMT1, is a member of a DNA methyltransferase (MTase) family. 17 It has three conserved domains: the PWWP domain targeting the enzyme to nucleic acids, the cystein-rich PHD zinc-finger domain interacting with unmodified histone H3, and the highly conserved catalytic domain representing the MTase domain in the Cterminal region. It has high ubiquitous expression in embryonic tissues and undifferentiated embryonic stem cells.…”

Basic concepts of epigenetics

“…[33][34][35] Methylation of CpG sites is performed by DNA methyltransferases DNMT3A and DNMT3B, which carry out de novo methylation, and DNMT1, which ensures heritable epigenome replication through cell division. 36 A closer look at DNMT1 shows that this enzyme not only methylates DNA, but also docks directly to methyl-CpG binding proteins (MBPs), such as MeCP2, MBD2 and MBD3. MBPs can equally dock to constrictive histone enzymes, such as histone deacetylases HDAC1 and HDAC2, human H3K9 methyltransferase (Suv39 h1) and heterochromatin protein 1 (HP1), all synergistic components of gene silencing.…”

Enzymatic Targets in Atherosclerosis

“…DNA methylation serves a wide variety of biological functions. An in-depth review of the mammalian DNMT family covering all the structural and mechanistic details is highly recommended to the reader [254]. DNMT1 (EC 2.1.1.37) is the key member of the family.…”