Memelilerde DNA metilasyon mekanizmasını belirleyen moleküler faktörler

DNA methylation is intrinsic to the integrity of diverse organisms due to the its impact on the genomic stability and gene expression. The most common type of DNA methylation occurs by transferring the methyl group of SAM to the C5 atom of cytosine nucleotide. The anew (de novo) and/or maintenance of DNA methylation patterns are imposed by the catalytic domain of DNA methyltransferases. The critical mutations occurring at this domain lead to developmental defects or cancer biogenesis. Thereby, discovering the working principles of DNA methyltransferases is crucial towards developing potent therapeutics combatting DNA methyltransferase malfunction. Mammals have three paralogous catalytically active DNA methyltransferases: DNMT1, DNMT3A and DNMT3B. DNMT3A/Bs predominantly take role in de novo methylation, while DNMT1 and/or DNMT3B maintain the pre-established DNA methylation pattern. Methylation site (CpG or non-CpG) preference of these enzymes is encoded in the flanking region surrounding the target cytosine. As an example, DNMT3A prefers -CAC- over -CAG- sequence, while the reverse is true for DNMT3B. Expanding on this notion, in this work, we aimed to investigate the mechanistic principles of DNMT3A/B enzymes with computational structural biology approaches. For this, we initially studied the structure of a DNA methyltransferase enzyme from a simple organism. This allowed us to define the evolutionary conserved structural elements of the DNA methyltransferases and to transfer them to mammalian DNMT3A/Bs. Besides, we also explored the stability, time-dependent intermolecular interaction networks and dynamics of DNMT3A/B:DNA complexes.