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Review
. 2016 Oct 14;44(18):8556-8575.
doi: 10.1093/nar/gkw723. Epub 2016 Aug 12.

Allosteric control of mammalian DNA methyltransferases - a new regulatory paradigm

Albert Jeltsch  1 , Renata Z Jurkowska  2
Affiliations
Review

Allosteric control of mammalian DNA methyltransferases - a new regulatory paradigm

Albert Jeltsch et al. Nucleic Acids Res. .

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.

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Figures

Figure 1.
Figure 1.
Domain structure of the mammalian DNMT enzymes. The human DNMT1, DNMT3A, DNMT3B and DNMT3L proteins consist of 1616, 912, 853 and 387 amino acid residues, respectively. Abbreviations used: DMAPD – DNA methyltransferase associated protein 1 interacting domain, PBD – PCNA binding domain, NLS – Nuclear localization signal, RFTD – Replication foci targeting domain, CXXC – CXXC domain, BAH1 and BAH2 – bromo-adjacent homology domains 1 and 2, GKn – glycine lysine repeats, PWWP – PWWP domain, ADD – ATRX-DNMT3-DNMT3L domain.
Figure 2.
Figure 2.
Structures of DNMT1 with different N-terminal domains. The RFT, CXXC, BAH1, BAH2 and catalytic domains are shown in dark green, red, orange, purple and blue, respectively. (A) DNMT1 in an active conformation with DNA (light green) bound in the active site (29). Removal of the autoinhibitory RFTD can be triggered by UHRF1 (40,41). (B) DNMT1 with unmethylated DNA bound to the autoinhibitory CXXC domain (43). (C) DNMT1 with the RFT domain blocking access to the active site (46).
Figure 3.
Figure 3.
Regulatory mechanisms controlling the activity, targeting and stability of DNMT1. The figure illustrates the complex interplay between DNMT1, UHRF1, USP7, PCNA and chromatin. Enzymatic activities are indicated by arrows. Binding (‘reading’) interactions are symbolized by dotted lines. For details cf. the text.
Figure 4.
Figure 4.
Representation of posttranslational modifications (PTMs) found in human DNMT1 on the structure of murine DNMT1 (46). Phosphorylations, acetylations, methylations and ubiquinations retrieved from Phosphosite Plus are represented by red circles labeled with P, A, M or U, respectively. The DNMT1 domains are colored as in Figure 2C.
Figure 5.
Figure 5.
Structure and allosteric regulation of DNMT3A. The picture shows the structure of the DNMT3A/3L heterotetramer (123). The ADD domain of the dark blue DNMT3A subunit is shown in the autoinhibitory conformation (orange) and in the catalytically active allosteric conformation (red) (113), the ADD domain of the cyan DNMT3A subunit has been omitted for clarity. Binding of the H3 peptide (purple) to the ADD domain occurs by interaction with residues, which are involved in the autoinhibitory-binding interface. Therefore, peptide binding is only possible in the active conformation and this conformation is consequently stabilized in the presence of the H3 peptide (113,122).
Figure 6.
Figure 6.
Multimerization of DNMT3A and DNMT3A/DNMT3L complexes. (A) Structure of the DNMT3A–DNMT3L complex with bound DNA. (B) Schematic model of multimerization of the DNMT3A/DNMT3L complexes on DNA. (C) Magnification of a part of B showing the access of active centers of the central DNMT3A subunits to both DNA strands of CpG sites (yellow boxes). (D) Schematic model of DNMT3A protein multimerization and binding to several DNA molecules. (E) Combination of both multimerization processes leading to the 2D multimerization of DNMT3A.
Figure 7.
Figure 7.
Mechanisms regulating the activity and localization of DNMT3A. Interactors and PTMs regulate the activity and localization in a concerted fashion. DNMT3L stimulates DNMT3A and promotes its euchromatic localization. Contrarily, CK2-mediated phosphorylation downregulates the activity of DNMT3A and promotes its heterochromatic localization, where the interaction with modified H3 tails could allosterically stimulate the enzyme.
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