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...
Autores principales: | , |
---|---|
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 |