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  • In general the DNMT encompass three different structural

    2020-02-13

    In general, the DNMT encompass three different structural regions: N-terminal regulatory domain, C-terminal catalytic domain and a central linker region (). The N-terminal regulatory domain is particularly implicated in determining subcellular localization of the DNMT and in allocating unmethylated DNA strands from hemi-methylated ones. The C-terminal catalytic domain consists of 10 different characteristic motifs, and six of them (I, IV, VI, VIII, IX and X) are evolutionally conserved among mammals. They have specific functions: while the motif I consists of an S-adenosyl-L-methionine (AdoMet) binding site, the motif IV can associate with the substrate hcv protease inhibitor at the active site. The motif VI is composed of glutamyl residues serving as a donor, the motif IX confers stability to the substrate-binding site and the motif X creates an AdoMet binding site; however, the function of motif VIII remains unclear. The third region of the DNMT, the central linker domain, involves repeated Lysine-Glycine (GK) dipeptides and provides a connection between the N- and C-terminal domains (Turek-Plewa and Jagodzinski, 2005) ().
    Particular functions of the DNMTs The most extensively studied DNMT type, DNMT1, is responsible for maintaining previously established DNA methylation marks after DNA replication, and it has a high affinity to hemi-methylated DNA strands (Cedar, Bergman, 2012, Pradhan et al, 1999). DNMT1 methylates the hemi-methylated DNA strands and ensures maintenance of the DNA methylation patterns during mitotic cell divisions (Cedar and Bergman, 2012). Interestingly, it has been revealed that DNMT1 partially contributes to the de novo methylation process independently from the de novo methyltransferases, DNMT3A and DNMT3B (Lorincz et al., 2002). To date, three functional DNMT1 isoforms have been identified: the pachytene spermatocyte form of DNMT1 (DNMT1p), the oocyte-specific form of DNMT1 (DNMT1o), and the somatic form of DNMT1 (DNMT1s) (Ko et al., 2005). Since all isoforms participate in the DNA methylation process, loss of Dnmt1 (Dnmt1−/−) causes embryonic lethality, lack of imprinting and extensive demethylation of the genome (Lei et al, 1996, Li et al, 1992) (). The DNMT3A and DNMT3B enzymes exclusively function in de novo methylation (Okano et al., 1998a). DNMT3B is additionally specialized for methylation of the CpG dinucleotides at the repeated DNA sequences present in the pericentric satellite parts of eukaryotic chromosomes (Kato et al, 2007, Okano et al, 1999). While DNMT3A has only two RNA isoforms, DNMT3B contains more than twenty RNA isoforms (Ostler et al., 2007). Dnmt3a and Dnmt3b knockout mice models exhibit embryonic lethality (Kaneda et al, 2004, Okano et al, 1999), genetic immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) in humans (Weemaes et al., 2013) (). Another member of the DNMT family, DNMT3L, does not have any methyltransferase catalytic activity (Chedin et al., 2002) because it lacks catalytic motifs in its structure (Turek-Plewa and Jagodzinski, 2005). However, it interacts with DNMT3A and DNMT3B to stimulate their activity (Neri et al., 2013). It is suggested that DNMT3L plays an important role in the establishment of maternal genomic imprints during oogenesis (Bourc\'his et al., 2001). Consistently, knockout of the Dnmt3L gene results in abnormal maternal imprinting and male infertility (Bourc\'his and Bestor, 2004) (). On the other hand, DNMT2 is able to methylate the cytosine 38 in the anticodon loop of aspartic acid transfer RNA instead of transferring methyl groups to the cytosine residues in the genomic DNA (Goll et al., 2006). Also, DNMT2 shows structural and functional differences when compared with the other DNMTs. For example, it does not include N-terminal domain, and therefore cannot contribute to de novo or maintenance methylation process (Turek-Plewa and Jagodzinski, 2005). Consistent with its basic mission, Dnmt2 knockout mice (Dnmt2−/−) exhibit disruption in the RNA methyltransferase activity (Goll et al, 2006, Okano et al, 1998b) ().