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Figure 1.5 Posttranslational modifications and regions of interactions of human DNMT1
with other proteins. Regions of DNMT1 defined in legend to
Fig. 1.4
. Posttranslational
modifications at serine (S) and lysine (K) residues are discussed in the text. Aportionof
the summary of interactions with other proteins is after
Sajedi et al. (2008)
.
the RFTS into the catalytic pocket of DNMT1, which is further stabilized
by the loop projecting from the BAH2 domain. In the presence of
hemimethylated DNA, the CXXC domain cannot interact with DNA
and as a result, the linker and the TS domain move away from the catalytic
domain. During this process, the catalytic cysteine undergoes a conforma-
tional change upon DNMT1 binding to
S
-adenosyl-
L
-methionine. Conse-
quently, the catalytic site gains access to DNA for methylation of the
daughter strand. Other CXXC-containing proteins such as CLF1 are also
known to bind to unmethylated DNA. CLF1 probably primarily functions
as a specificity factor to direct trimethylation of histone H3 at lysine 4
(H3K4me3) to CpG-rich gene-regulatory regions. Interestingly, a defi-
ciency of CLF1 in mouse ES cells phenocopies the severe loss of genomic
methylation observed in DNMT1-null ES cells (
Carlone et al., 2005; Lei
et al., 1996
). How a deficiency of CLF1 leads to a loss of genomic CpG
methylation is not entirely clear, but the most likely explanation is that loss
of CLF1 permits the “leakage” of H3K4me3 and associated CpG demeth-
ylation to chromatin and genomic areas normally devoid of H3K4me3
(
Clouaire et al., 2012; Tate et al., 2009
).
From the above discussion, we can conclude that the process of recog-
nition of hemimethylated DNA by DNMT1 involves both catalytic and
recognition loops that interact with both grooves containing the methylated
cytosine and the unmethylated cytosine that is everted from the double
helix. The combination of autoinhibitory and active mechanisms brings
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