Functions of DNA Methylation and Hydroxymethylation in Mammalian Development - Current Topics in Developmental Biology - page 49

A

1616 aa

DNMT1 h

PCNA-binding domain
Poly-KG linker
Replication foci-targeting domain

912 aa
853 aa

DNMT3A h
DNMT3B h
DNMT3L h 386 aa

PWWP domain
CXXC domain
Bromo-adjacent homology (BAH) domain
Cys-rich ADD domain

DNMT1 m 1620 aa

DNMT3A m 908 aa

DNMT3B m 859 aa

Catalytic domain

DNMT3L m 421 aa

B

TET1 h 2136 aa

TET2 h 2002 aa CXXC domain

Cys-rich domain

1660 aa

TET3 h

Double-stranded b -helix (DSBH) 2OG-Fe(II)-
dependent dioxygenase domain

2039 aa

TET1 m

Fe(II) binding
2-Oxoglutarate binding

1912 aa

TET2 m

TET3 m 1668 aa

Figure 2.2 Structure of mammalian DNMT and TET enzymes. (A) DNMTs share a
C-terminal catalytic domain, except DNMT3L which does not contain a functional cat-
alytic domain. The N-terminal part of DNMT1 contains interaction domains with PCNA,
replication foci, and unmethylated DNA (CXXC domain). DNMT1 also contains two BAH
domains. DNMT3A and DNMT3B comprise a PWWP domain recognizing H3K36me3 and
an ADD domain mediating interaction with histone H3 unmethylated at H3K4. (B) TET
proteins contain in their C terminus a cysteine-rich domain adjacent to a DSBH domain
typical of 2-oxoglutarate-Fe(II)-dependent dioxygenases. TET1 and TET3 also contain a
CXXC domain. The size of the proteins is indicated by the number of amino acids (aa).

replication during S phase and is preferentially active on hemimethylated
CpGs generated after replication ( Arand et al., 2012; Leonhardt, Page,
Weier, & Bestor, 1992 ). In mice, the absence of DNMT1 leads to global
genome hypomethylation, increase of hemimethylated CpG sites, failure
to maintain methylation imprints, and early embryonic death ( Arand
et al., 2012; Hirasawa et al., 2008; Kurihara et al., 2008; Lei et al., 1996 ).
DNMT1 works as part of a complex as it contains a PCNA-binding domain
and also interacts with UHRF1 (also known as NP95), a factor that binds
hemimethylated CpGs and is required to recruit DNMT1 at sites of hem-
imethylation ( Bostick et al., 2007; Sharif et al., 2007 ). TheN-terminal part of
the protein contains two bromo-adjacent homology domains (BAH1 and
BAH2), as well as a CXXC-type zinc-finger domain also found in other
chromatin regulators such as MLL, CFP1, MBD1, KDM2A/B, and TET1
( Fig. 2.2 A). Similar to MLL, CFP1, or MBD1, the DNMT1 CXXC domain