Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm

Abstract

In mammals, DNA methylation is introduced by the DNMT1, DNMT3A and DNMT3B methyltransferases, which are all large multi-domain proteins containing a catalytic C-terminal domain and an N-terminal part with regulatory functions. Recently, two novel regulatory principles of DNMTs were uncovered. It was shown that their catalytic activity is under allosteric control of N-terminal domains with autoinhibitory function, the RFT and CXXC domains in DNMT1 and the ADD domain in DNMT3. Moreover, targeting and activity of DNMTs were found to be regulated in a concerted manner by interactors and posttranslational modifications (PTMs). In this review, we describe the structures and domain composition of the DNMT1 and DNMT3 enzymes, their DNA binding, catalytic mechanism, multimerization and the processes controlling their stability in cells with a focus on their regulation and chromatin targeting by PTMs, interactors and chromatin modifications. We propose that the allosteric regulation of DNMTs by autoinhibitory domains acts as a general switch for the modulation of the function of DNMTs, providing numerous possibilities for interacting proteins, nucleic acids or PTMs to regulate DNMT activity and targeting. The combined regulation of DNMT targeting and catalytic activity contributes to the precise spatiotemporal control of DNMT function and genome methylation in cells.

5‐Methylcytosine is Oxidized to the Natural Metabolites of TET Enzymes by a Biomimetic Iron(IV)‐Oxo Complex

“…[1] The hereby formed 5-methyl cytosine (5mC),a ne pigenetic marker,i st hen removed throught wo major pathways:a ctive and passive demethylation. [1] The hereby formed 5-methyl cytosine (5mC),a ne pigenetic marker,i st hen removed throught wo major pathways:a ctive and passive demethylation.…”

Hypoxic‐stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non‐small cell lung cancer

“…DNA methylation occurs primarily at the 5-position of cytosine in CpG dyads, and their genomic methylation patterns are established and maintained by DNA methyltransferases (DNMTs). Of the known vertebrate DNMTs, DNMT3a and DNMT3b showed equal cytosine-5 methylation activities toward unmethylated and hemimethylated DNA substrates, and they were classically designated de novo genomic DNMTs (25,26). DNMT1 shows a substrate preference for hemimethylated DNA and maintains the methylation patterns during DNA replication (25,26).…”

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

“…Another approach to inhibit DNMT activity is to target the protein–protein interactions (PPI) needed for the interaction of the enzyme with its partners [8,20]. Earlier in this paper, two interactions were discussed: H3K36me3 recognized by the PWWP domain of DNMTs, and unmodified H3 recognized by the ADD domain of DNMT3a [1,7,14].…”

“…In addition, a clustered regularly interspaced palindromic repeat clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system was proven to affect the DNA methylation pattern, and it may represent a novel profitable approach [151]. Disruption of PPIs in DNMT-involving complexes represents a very specific and targeted cancer treatment approach [8]. …”

“…They also share an N -terminal domain that contains the ADD (ATRX-DNMT3-DNMT3L) motif and the nucleosome recognition PWWP (Pro-Trp-Trp-Pro) motif. These motifs are responsible for the interaction with DNA and with proteins that guide the enzymes to the nucleus, the chromatin and the DNA [2,7,8]. DNMT3L does not show a catalytic activity as it lacks the catalytic domain.…”