Beyond Watson and Crick: DNA Methylation and Molecular Enzymology of DNA Methyltransferases

Abstract

DNA methyltransferases catalyze the transfer of a methyl group from S-adenosyl-L-methionine to cytosine or adenine bases in DNA. These enzymes challenge the Watson/Crick dogma in two instances: 1) They attach inheritable information to the DNA that is not encoded in the nucleotide sequence. This so-called epigenetic information has many important biological functions. In prokaryotes, DNA methylation is used to coordinate DNA replication and the cell cycle, to direct postreplicative mismatch repair, and to distinguish self and nonself DNA. In eukaryotes, DNA methylation contributes to the control of gene expression, the protection of the genome against selfish DNA, maintenance of genome integrity, parental imprinting, X-chromosome inactivation in mammals, and regulation of development. 2) The enzymatic mechanism of DNA methyltransferases is unusual, because these enzymes flip their target base out of the DNA helix and, thereby, locally disrupt the B-DNA helix. This review describes the biological functions of DNA methylation in bacteria, fungi, plants, and mammals. In addition, the structures and mechanisms of the DNA methyltransferases, which enable them to specifically recognize their DNA targets and to induce such large conformational changes of the DNA, are discussed.

The fetal origins of memory: The role of dietary choline in optimal brain development

“…70 When this modification occurs in promoter regions, gene expression is altered; 71 increased methylation is associated with gene silencing or reduced gene expression. 70 In cholinedeficient cells in culture, methylation of the cyclindependent kinase inhibitor 3 gene promoter is decreased, resulting in overexpression of this gene, which inhibits cell proliferation. 72 We replicated this observation in brains of fetuses from choline-deficient mothers and found that cyclin-dependent kinase inhibitor 3 was hypomethylated and overexpressed in the neuroepithelium of the fetal hippocampus (submitted for publication); we suggest that this is the likely molecular mechanism for decreased stem cell proliferation in brains of these fetuses.…”

Bacterial DNA activates human neutrophils by a CpG‐independent pathway

“…Prokaryotes contain DNA with N 6 -methyladenine, 5-methylcytosine, and N 4 -methylcytosine because of the presence of adenine-and cytosine-DNA methyltransferases [21]. In contrast, adenine-methyltransferases have not been described in higher eukaryotes, in which only cytosine-C5 methylation has been found.…”

“…In contrast, adenine-methyltransferases have not been described in higher eukaryotes, in which only cytosine-C5 methylation has been found. Moreover, cytosine methylation in mammals mainly occurs at CG sequences [21]. To determine whether content of adenine methylation or cytosine methylation other than CG methylation in bacterial DNA may account for its stimulatory capacity, we used bacterial DNA isolated from an E. coli strain deficient in both adenine and cytosine methyltransferases (E. coli SCS110 strain Dam -Dcm -).…”

Mechanistic details of the DNA recognition by the Dnmt1 DNA methyltransferase

“…1). Like in all other structures of DNA MTases with substrate DNA [4][5][6][7] and initially discovered with M.HhaI [8], the target Cyt is rotated out of the DNA helix and bound to a pocket in the protein, which presents the active site residues conserved among DNA-(cytosine C5)-methyltransferases [4,7]. Unexpectedly, in the Dnmt1-DNA structure the orphan Gua residue from the non-target strand forms a base pair with a Gua from a Gua:Cyt base pair 5 0 of the CpG site.…”