Cargando…

Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Jeltsch, Albert, Jurkowska, Renata Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062992/
https://www.ncbi.nlm.nih.gov/pubmed/27521372
http://dx.doi.org/10.1093/nar/gkw723
_version_ 1782459891521159168
author Jeltsch, Albert
Jurkowska, Renata Z.
author_facet Jeltsch, Albert
Jurkowska, Renata Z.
author_sort Jeltsch, Albert
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5062992
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-50629922016-10-14 Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm Jeltsch, Albert Jurkowska, Renata Z. Nucleic Acids Res Survey and Summary 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. Oxford University Press 2016-10-14 2016-08-12 /pmc/articles/PMC5062992/ /pubmed/27521372 http://dx.doi.org/10.1093/nar/gkw723 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Survey and Summary
Jeltsch, Albert
Jurkowska, Renata Z.
Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm
title Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm
title_full Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm
title_fullStr Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm
title_full_unstemmed Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm
title_short Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm
title_sort allosteric control of mammalian dna methyltransferases – a new regulatory paradigm
topic Survey and Summary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062992/
https://www.ncbi.nlm.nih.gov/pubmed/27521372
http://dx.doi.org/10.1093/nar/gkw723
work_keys_str_mv AT jeltschalbert allostericcontrolofmammaliandnamethyltransferasesanewregulatoryparadigm
AT jurkowskarenataz allostericcontrolofmammaliandnamethyltransferasesanewregulatoryparadigm