Evolutionary and structural insights into DNMTs and TETs: decoding their functional heterogeneity and oncogenic roles in methylation regulation

DNA methylation in mammals is dynamically regulated by DNMTs and TETs. Despite their critical roles, comparative structural analyses of these protein families have been relatively scarce. To address the above problems, this study first constructed a phylogenetic tree of DNMT and TET proteins to investigate their evolutionary relationships. Furthermore, the structural exploration revealed that both protein families possess conserved β-sheet structures and exhibit the characteristics of alternating β-sheets in their catalytic domains. Interestingly, DNMTs contain more α helices and fewer loops compared to TETs. Several notable structural changes were discovered, including unique flexibility of the CXXC domain and divergences in DNA binding mechanisms among DNMT1, TET1, and TET3. Additionally, the results showed that a distinctive loop present in DNMT2 may indicate its specialized functional role. This research provides fundamental evolutionary and structural insights into DNMT and TET proteins, emphasizing their significance in tissue-specific distribution and cancer signaling, thereby establishing a foundation for future investigations in the field of epigenetics.