Abstract
DNA methylation, one of the major epigenetic mechanisms, plays critical roles in regulating gene expression, genomic stability and cell lineage commitment. The establishment and maintenance of DNA methylation in mammals is achieved by two groups of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B, which are responsible for installing DNA methylation patterns during gametogenesis and early embryogenesis, and DNMT1, which is essential for propagating DNA methylation patterns during replication. Both groups of DNMTs are multi-domain proteins, containing a large N-terminal regulatory region in addition to the C-terminal methyltransferase domain. Recent structure-function investigations of the individual domains or large fragments of DNMT1 and DNMT3A have revealed the molecular basis for their substrate recognition and specificity, intramolecular domain-domain interactions, as well as their crosstalk with other epigenetic mechanisms. These studies highlight a multifaceted regulation for both DNMT1 and DNMT3A/3B, which is essential for the precise establishment and maintenance of lineage-specific DNA methylation patterns in cells. This review summarizes current understanding of the structure and mechanism of DNMT1 and DNMT3A-mediated DNA methylation, with emphasis on the functional cooperation between the methyltransferase and regulatory domains.
Highlights
DNA methylation represents one of the major epigenetic mechanisms that critically influence gene expression and cell fate commitment [1,2,3,4,5,6]
Methyltransferase appears to be an oversimplification, as increasing evidence has revealed an important role of DNMT3A and DNMT3B in DNA methylation maintenance [19,20], while other studies have pointed to the de novo methylation activity of DNA methyltransferase 1 (DNMT1) in specific loci [21,22]
At one endmDNMT1-unmethylated of the DNA, the CXXC domain interacts with the DNAtwo molecule from both the interfaces, one located in the domain and the other located in the Atinto one end major groove and the minor groove, with a loop segment (R684-S685-K686-Q687) penetrating of thethe
Summary
DNA methylation represents one of the major epigenetic mechanisms that critically influence gene expression and cell fate commitment [1,2,3,4,5,6]. Rossmann fold, which consists of a mixed seven-stranded a conserved catalytic core termed Rossmann fold, which consists of a mixed seven-stranded β-sheet β-sheet flanked three α-helices on either side [24] These enzymes catalyze thereaction methylation flanked by three by α-helices on either side [24]. S-adenosyl-L-methionine (AdoMet)-dependent manner, with the catalytic core harboring essential essential motifs for enzymatic catalysis and cofactor binding. This review the recent an progress in structural mechanistic of DNMT1 and DNMT3A, with an provides overview on the and recent progress understanding in structural and mechanistic understanding of emphasis on how the regulatory and MTase domains of each enzyme cooperate in maintenance and DNMT1 and DNMT3A, with an emphasis on how the regulatory and MTase domains of each de novo cooperate. Regulator DNMT3L, with individual domains marked by residue numbers
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