Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 6

2005; Law and Jacobsen, 2010 ). HemimethylatedDNA is normally a chemical
intermediate during replication of fully methylated parental DNA to fully
methylated progeny DNA, and its role in transcriptional repression is less clear.
An alternative possible purpose of hemimethylated DNA will be
discussed below.
A highly relevant aspect of symmetric cytosine methylation becomes
clear when the effects of DNA replication on methylation are considered.
DNA replication of fully methylated DNA results in two hemimethylated
double-helical daughter DNA strands. One is methylated on one parental
strand and the other is methylated on the opposite parental strand. Although
chemically different (e.g., the DNA sequence flanking the methylated cyto-
sines is usually different), the two progeny double helices are related in very
important ways—each double helix retains exactly one-half of the original
methylation seen in the fully methylated parental double helix, the retained
methylation is completely on CpG dinucleotides and/or CpHpG trinucle-
otides, and all originally fully methylated di- or trinucleotides are now
hemimethylated. This result is very different than what occurs with replica-
tion of asymmetrically methylated DNA—in this case, two different double
helices are synthesized, but at any given originally methylated trinucleotide
sequence, only one of the progeny double helices is methylated, the other is
now fully unmethylated.
2.3. Holliday/Pugh and Riggs postulates for inheritance
of symmetric cytosine methylation
The above discussion leads us to consider that symmetrically methylated
DNA has a function that asymmetrically methylated DNA does not, and that
the unique function of symmetrically methylated DNA is related to the
hemimethylated state of base-paired di- and trinucleotides found immedi-
ately after replication. In the mid-1970s, Robin Holliday and J. E. Pugh
and independently Arthur Riggs postulated that hemimethylated symmetric
DNA could activate an enzymatic activity (E2 in Fig. 1.2 ) that would con-
vert it to a fully methylated form, returning the pattern of epigenetic mod-
ification to its original parental form, thus acting as a mechanism of
epigenetic inheritance ( Holliday and Pugh, 1975; Riggs, 1975 ). We now
refer to this E2 enzymatic activity as maintenance methylation or mainte-
nance methyltransferase activity. Maintenance methyltransferases generi-
cally act to maintain methylation on fully methylated genomic DNA
regions following their replication. These enzymes perform this function
within a two-step process whereby hemimethylated di- or trinucleotides