Ch3 ch3

DNMT

Replication complex

Replication complex

DNMT

ch3

Figure 11.2 Schematic representation of de novo and maintenance methylation events. Two types of methylation activity are required in cells. (A) De novo methylation refers to the addition of methyl groups by DNMTs on an unmethylated substrate; this occurs mainly within CpG dinucleotides (i.e. the 3' carbon atom of the cytosine is linked by a phosphodiester bond to the 5' carbon atom of the guanine - left inset). (B) Following DNA replication, DNMTs performing maintenance methylation are responsible for adding methyl groups to the newly synthesized daughter strands at positions opposite to the methyl groups present on the parent strand, ensuring stable transmission of DNA methylation patterns following cell division preimplantation stage embryos are established by DNMTs with de novo methyl-transferase activity, whereas differentiated cells present very little propensity to de novo methylation (Lei et al., 1996). DNMTs with maintenance activity are required to ensure the accurate propagation of DNA methylation patterns at the time of cell division by faithfully copying the methylation status of the mother strand onto the daughter strand after replication.

All of the known mammalian DNMTs share similarities in their C-terminal catalytic domain, characterized by the 10 conserved amino acid motifs implicated in their catalytic function (reviewed by Bestor, 2000; Goll and Bestor, 2004; Hermann et al, 2004). In addition, DNMT1, DNMT3a and DNMT3b contain large N-terminal regulatory domains (Fig. 11.3, Color plate 10). The mammalian DNMTs show little evidence of specificity for selected DNA sequences and thus how and why certain sequences become methylated has been a longstanding question in the field (for review, see Goll and Bestor, 2004). An equally important question is what prevents certain sequences from becoming methylated at different times. Recent results suggest that methylation of DNA at specific sites is the result of multiple inputs including the presence of repeat sequence elements in the DNA, interactions between RNA and DNA and histone modifications; precisely how these different mechanisms interact in germ cells to target specific sequences for methylation is unknown and an important area for future studies. Mouse gene-targeting studies have been particularly useful in shedding light on the biological functions of the different DNMTs. In

Cys-rich Catalytic domain od6T,'„I i'I ivg=n

DNMT3b (859 aa)

IV VI IX X

DNMT2 i!

Cys-rich

Figure 11.3 Organization of known mammalian DNMTs. Specific motifs are represented by boxes;

five of the important amino acid motifs involved in catalysis are illustrated to demonstrate homology in the catalytic domain. Sizes in amino acids (aa) are those of the murine proteins (see Color plate 10)

the following section, current knowledge on the DNMTs from mouse, bovine and human studies will be reviewed, including their expression in germ cells and early embryos, as well as the reproductive consequences of their disruption.

U.4 DNMT1

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