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mediates binding to DNA containing unmethylated CpGs (
Frauer et al.,
2011
). This CXXC domain has also been shown to create an autoinhibitory
conformational change that prevents interaction of DNA with the catalytic
domain when DNMT1 is bound to unmethylated CpGs but not
hemimethylated CpGs, therefore providing a mechanism to explain the pref-
erence of DNMT1 for hemimethylated over unmethylated DNA (
Song,
Rechkoblit, Bestor, & Patel, 2011; Song, Teplova, Ishibe-Murakami, &
Patel, 2012
).
DNMT3A and DNMT3B are responsible for establishing DNA methyl-
ation
de novo
during development (
Okano, Bell, Haber, &Li, 1999
;
Fig. 2.1
B).
DNMT3B is abundant in early embryos and is themain enzyme responsible for
the gain of DNAmethylation after implantation (
Borgel et al., 2010
), whereas
DNMT3A is more prevalent in differentiated cells. Accordingly,
Dnmt3b
/
mice die during gestation, whereas
Dnmt3a
/
mice survive until birth but
most of themdie around 4weeks of age (
Okano et al., 1999
). DNMT3A is also
critical for the establishment of DNA methylation imprints in the germ line
(
Kaneda et al., 2004; Kato et al., 2007
). The combined knockout of DNMT3A
and DNMT3B leads to a more severe phenotype and all embryos die before
E11.5 due to impaired gastrulation, suggesting that both enzymes play syner-
gistic functions during early development (
Okano et al., 1999
). Besides their
activity as
de novo
methyltransferases, DNMT3A andDNMT3B also cooperate
with DNMT1 to efficiently maintain DNA methylation during replication at
sitesthatweremissedbyDNMT1(
Arand et al., 2012; Jones & Liang, 2009
).
This is illustrated by the fact that DNMT3A/B-deficient embryonic stem (ES)
cells showan increased proportion of hemimethylatedCpG sites and a progres-
sive loss of methylation upon cell division (
Liang et al., 2002
). The last member
of the family, DNMT3L, lacks crucial amino acids required for a functional
catalytic domain (
Fig. 2.2
A). DNMT3L is highly expressed in germ cells
and seems to exert its function mostly in the germ line.
Dnmt3L
/
mice
are viable and proceed normally through development but fail to establish
DNAmethylation in themale and female germ line, which translates intomale
sterility (
Bourc'his & Bestor, 2004; Bourc'his, Xu, Lin, Bollman, & Bestor,
2001; Kato et al., 2007; Kobayashi et al., 2012; Smallwood et al., 2011
).
The role of DNMT3L, despite the absence of a functional catalytic domain,
is explained by the fact that DNMT3L acts as a cofactor for the DNMT3
enzymes and stimulates their activity (
Chedin, Lieber, & Hsieh, 2002;
Gowher, Liebert, Hermann, Xu, & Jeltsch, 2005; Jia, Jurkowska, Zhang,
Jeltsch, & Cheng, 2007; Ooi et al., 2007
). DNMT3A and DNMT3B contain
aPWWPdomain(
Fig. 2.2
A) that interacts with histoneH3 lysine 36 (H3K36)
