DNA methyltransferases (DNMTs) are the writers of the epigenome. DNMTs are a highly conserved family of proteins present in nearly all life on earth. In mammals, there are 3 major DNMTs: DNMT1, DNMT3a and DNMT3b. DNMT1 is a maintenance DNMT, while DNMT3a and 3b are de novo DNMTs. The common feature of all 5C-DNMTs is 10 conserved amino acids in their C-terminal catalytic domain. They also have10 conserved motifs that fulfill catalytic, cofactor binding, and DNA targeting functions (Bestor, 2000).
DNMT1 is the most abundant DNMT in adult cells (Robertson et al., 1999). It binds to hemi-methylated DNA (DNA with only one stand methylated), at CpG sties. After DNA replication, while the parent strand remains methylated the newly synthesized strand is not. DNMT1 binds to these hemi-methylated CpG sites and methylated the cytosine on the newly synthesized stand. This maintains established CpG methylation patterns through mitosis.
The de novo DNA methyltransferases DNMT3a and DNMT3b do not require hemi-methylated DNA to bind, they show equal affinity for hemi-methylated and non-methylated DNA (Okano et al., 1998). The DNMT3 enzymes are required for the genome-wide de novo methylation of DNA that occurs after embryo implantation. Both DNMT3a and DMNTb are essential for early development, and the loss of either is lethal (Okano et al., 1999). The DNMT3 group also includes a catalytically inactive member, DNMT3L. Just because it is not active doesn’t mean it isn’t important however. DNMT3L is essential for development, and when bound to DNMT3a/b, it increases their catalytic activity 15-fold (Gowher et al., 2005).
It should be noted that the maintenance vs. de novo function of these enzymes is not absolute. DNMT1 can function as a de novo DNMT; overexpression of DNMT1 leads to de novo methylation of CpG islands (Vertino et al., 1996). Similarly, DNMT3a/b can fill the role of a maintenance DNMT; human cancer cells lacking DNMT1 have shown only a 20% reduction in methylation of CpG sties (Rhee et al., 2000).
There is another DNMT in vertebrates, DNMT2. DNMT2 shares strong sequence homology to the other DNMTs, but has a barley any detectable DNA-cysteine methylation activity (Jeltsch et al., 2006). Its role in DNA methylation remains unclear. DNMT2 does appear to have significance in methylation of tRNA. DNMT2 has been shown to specifically methylate cytosine 38 of transfer RNAAsp (Goll et al., 2006). Methylation of tRNAs has an impact on the folding and stability of the structure (Alexandrov et al., 2006). DNMT2 has since been shown to methyl other tRNAs and that this may serve a protective function (Schaefer et al., 2010). Researchers are currently examining whether DNMT2 acts on other small RNAs.
Recently, it has be demonstrated that DNMTs can also act as demethylases. Mammalian DNMT1, DNMT3a, and DNMT3b can all convert 5mC to cytosine. This enzymatic processes is dependent on both a Ca2+ ion and a reducing environment (Chen et al., 2013). This process is essentially the enzymatic reverse of the Cà5mC reaction that the enzymes classically catalyze, a stark contrast to the iterative demethylation of 5mC by the TET enzymes. Increased Ca2+ ion concentration in the early zygote coincides with the period of active demethylation (Sardet et al., 1998). Future work is need to ascertain if active demethylation is carried out by DNMTs in vivo however.
DNA Methyltransferase Additional Reading
This review examines what is known and unknown about DNMT2. It addresses recent advances in our understanding of the enzymes and make some inferences about how it may be important in human disease.
This review introduces DNMT inhibitors and their mechanism of action. It focuses on how there inhibitors may serve as anti-cancer therapies, particularly the two approved for use but also other classes of up-and-coming possibilities.
This review covers in detail the structure of the mammalian DNMT genes and proteins. This is an older review, but what it covers hasn’t changed a great deal since its publication.
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