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Fig. 3 | Epigenetics & Chromatin

Fig. 3

From: DNA methylation and DNA methyltransferases

Fig. 3

Structure and regulation of DNMT1. a Functional domains in DNMT1. A nuclear localization sequence (NLS) and replication focus targeting sequence (RFTS) are closest to the N-terminus. A CXXC domain binds selectively to unmethylated CpG dinucleotides; this binding event interposes an acidic autoinhibitory loop between the active site and unmethylated DNA to inhibit de novo methylation [30]. The bromo-adjacent homology (BAH) domains 1 and 2 are of unknown function but are related in structure to BAH domains in other proteins that bind to specific modified histones (reviewed in [39]). A run of alternating lysine and glycine residues joins the multidomain N-terminal domain to the large C-terminal methyltransferase domain, which is related in sequence and structure to all other DNA (cytosine-5) methyltransferases (reviewed in [35]). Letters below the diagram indicate the position of N-terminal truncations in the crystal structures shown in be. b Superposition of the structures of active DNMT1 [30] and M.HhaI, a bacterial restriction methyltransferase [40]. The methyltransferase domain of DNMT1 shows strong isostery with full-length M.HhaI. c Superposition of autoinhibited DNMT1 in complex with unmethylated DNA and active DNMT1 deleted for the CXXC and autoinhibitory loop domains in complex with hemimethylated DNA [41]. DNA can be seen to have accessed the catalytic pocket of DNMT1 in the active complex and to be very close to the S-adenosyl-l-homocysteine present in both complexes. d, e Impingement of the RFTS on the CXXC domain displaces the latter (curved arrow) into a conformation that inhibits binding of DNA [42]. It is proposed that the interaction of UHRF1 bound to hemimethylated DNA causes a retraction of the RFTS domain to allow access of hemimethylated DNA to the active site of DNMT1 [42]

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