Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 3

and all mammalian species is restricted to the 5 0 -CpG-3 0 dinucleotide in a sym-
metric context. Because of this symmetry, CpG methylation allows faithful
inheritance of methylation patterns from a mitotically active parent cell. Meth-
ylation's role as a formof heritable information is most interesting because of its
importance in regulating developmental processes, including genomic
imprinting in mammals. Imprinted genes regulate mammalian development
through a diverse set of sometimes complex molecular “interpretations” of
inherited methylation. In some instances, imprinted methylation is associated
with gene silencing, whereas in other instances inherited methylation is asso-
ciated with active transcription ( Bartolomei and Tilghman, 1997 ).
Levels and positions of methylated cytosines are not constant in genomes
of mammalian species. Rather, they change through processes of demeth-
ylation and de novo methylation in predictable ways during the organisms'
life cycles. Cytosine methyltransferase enzymes participate in defining geno-
mic locations of cytosine methylation and importantly their changes during
life cycles. The activities of these enzymes underlie in part the establishment
of cytosine methylation on unmethylated DNA ( de novo methylation), the
perpetuation or maintenance of genomic methylation patterns over devel-
opmental time, and possibly demethylation, or the loss of genomic methyl-
ation within specific windows of developmental time.
TheDNAmethyltransferase1(DNMT1)enzymeisthevertebratemainte-
nance methyltransferase. DNMT1 catalyzes the maintenance of patterns of
genomic methylation andmay also be involved in the process of demethylation.
If DNMT1 indeed possesses both activities, it would be central to remodeling of
genomic methylation patterns known to occur during development. For these
reasons, we will now carefully explore important aspects of the cell and molec-
ular biology of theDNMT1 protein, in particular, focusing onmolecular mech-
anisms known to regulate its enzymatic activity, stability, and expression.
2. POSITIONS OF GENOMIC 5-METHYL-CYTOSINES
AND THEIR SIGNIFICANCE
2.1. Symmetric and asymmetric cytosine methylation
in plants and animals
Methylation of DNA bases is the only known primary covalent modification
of DNA and methylation is confined to cytosine bases in eukaryotic species.
Although further modification of methylated cytosine bases, for example, to
5-hydroxymethylcytosine (5-hmC) can occur, there is no evidence that