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Allosteric control of mammalian DNA methyltransferases - a new regulatory paradigm

Jeltsch, Albert and Jurkowska, Renata Z. ORCID: 2016. Allosteric control of mammalian DNA methyltransferases - a new regulatory paradigm. Nucleic Acids Research 44 (18) , pp. 8556-8575. 10.1093/nar/gkw723

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Publisher: Oxford University Press (OUP)
ISSN: 0305-1048
Date of First Compliant Deposit: 31 October 2019
Date of Acceptance: 8 October 2016
Last Modified: 03 May 2023 21:18

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