Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 19

serine 146 and at other sites subsequent to the phosphorylation at serine 146
( Sugiyama et al., 2010 ). Serine 146 phosphorylation results in a decreased
affinity of DNMT1 to its target DNA. Phosphorylation at serine 515 has
been suggested to be important for the interaction of the N-terminal and
catalytic domains and is required for the enzymatic function of DNMT1
( Goyal et al., 2007 ). Abolishment of this phosphorylation site resulted in
absence of catalytic activity although the enzyme could still bind DNA.
PKC and/or AKT phosphorylates serine 127 and serine 143 in cancer cells
and the phosphorylated DNMT1 is unable to bind PCNA and UHRF1
( Hervouet et al., 2010 ). As a result, DNMT1 cannot bind to its target sites
leading to global hypomethylation involving repeat elements leading to
genomic instability and local hypomethylation at loci such as PDGF-B ,
H-RAS , and MGMT .
In addition to modification of DNMT1 by phosphorylation, posttransla-
tional modification of DNMT1 by lysine methylation has also been shown to
be important ( Est`ve et al., 2009 ). SET7 which is a histone methyltransferase
also methylates DNMT1 at lysine 142. This methylation peaks during the
S and G2 phases and is subjected to proteasome-mediated degradation.
LSD1 which demethylates at H3K9 and H3K4 residues also demethylates
DNMT1 leading to its stability ( Wang et al., 2009 ). Loss of LSD1 results
in DNMT1 instability and genomic hypomethylation. Thus, methylation
at lysine 142 and phosphorylation at serine 143 are mutually exclusive events
that together determine the stability of the DNMT1 enzyme.
DNMT1 has been shown to have multiple sites for SUMOylation and like
other SUMOylated proteins ( Lee and Muller, 2009 ), DNMT1 also interacts
withUbc9, the sole conjugating enzyme for SUMOylation. Ubc9 interactions
were mapped to the region corresponding to residues 645-1113 containing
two BAH domains which are also involved in targeting of DNMT1 to rep-
lication foci. It has been suggested that DNMT1 is SUMOylated when it is
methylating the heterochromatic regions, consistent with the fact that SUMO
proteins are abundant in the heterochromatic regions.
4. GENOMIC METHYLATION DURING PLANT
AND ANIMAL LIFE CYCLES
4.1. Patterns of symmetric methylation during
mouse development
For proliferating cells, as best exemplified by a cell line in culture in which
the specific patterns of genomic methylation remain constant, the role of
maintenance methylation is obvious. As well, the genetic removal of