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DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation

DNA methylation maintenance by DNMT1 is an essential process in mammals but molecular mechanisms connecting DNA methylation patterns and enzyme activity remain elusive. Here, we systematically analyzed the specificity of DNMT1, revealing a pronounced influence of the DNA sequences flanking the targe...

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Autores principales: Adam, Sabrina, Anteneh, Hiwot, Hornisch, Maximilian, Wagner, Vincent, Lu, Jiuwei, Radde, Nicole E., Bashtrykov, Pavel, Song, Jikui, Jeltsch, Albert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381644/
https://www.ncbi.nlm.nih.gov/pubmed/32709850
http://dx.doi.org/10.1038/s41467-020-17531-8
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author Adam, Sabrina
Anteneh, Hiwot
Hornisch, Maximilian
Wagner, Vincent
Lu, Jiuwei
Radde, Nicole E.
Bashtrykov, Pavel
Song, Jikui
Jeltsch, Albert
author_facet Adam, Sabrina
Anteneh, Hiwot
Hornisch, Maximilian
Wagner, Vincent
Lu, Jiuwei
Radde, Nicole E.
Bashtrykov, Pavel
Song, Jikui
Jeltsch, Albert
author_sort Adam, Sabrina
collection PubMed
description DNA methylation maintenance by DNMT1 is an essential process in mammals but molecular mechanisms connecting DNA methylation patterns and enzyme activity remain elusive. Here, we systematically analyzed the specificity of DNMT1, revealing a pronounced influence of the DNA sequences flanking the target CpG site on DNMT1 activity. We determined DNMT1 structures in complex with preferred DNA substrates revealing that DNMT1 employs flanking sequence-dependent base flipping mechanisms, with large structural rearrangements of the DNA correlating with low catalytic activity. Moreover, flanking sequences influence the conformational dynamics of the active site and cofactor binding pocket. Importantly, we show that the flanking sequence preferences of DNMT1 highly correlate with genomic methylation in human and mouse cells, and 5-azacytidine triggered DNA demethylation is more pronounced at CpG sites with flanks disfavored by DNMT1. Overall, our findings uncover the intricate interplay between CpG-flanking sequence, DNMT1-mediated base flipping and the dynamic landscape of DNA methylation.
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spelling pubmed-73816442020-07-28 DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation Adam, Sabrina Anteneh, Hiwot Hornisch, Maximilian Wagner, Vincent Lu, Jiuwei Radde, Nicole E. Bashtrykov, Pavel Song, Jikui Jeltsch, Albert Nat Commun Article DNA methylation maintenance by DNMT1 is an essential process in mammals but molecular mechanisms connecting DNA methylation patterns and enzyme activity remain elusive. Here, we systematically analyzed the specificity of DNMT1, revealing a pronounced influence of the DNA sequences flanking the target CpG site on DNMT1 activity. We determined DNMT1 structures in complex with preferred DNA substrates revealing that DNMT1 employs flanking sequence-dependent base flipping mechanisms, with large structural rearrangements of the DNA correlating with low catalytic activity. Moreover, flanking sequences influence the conformational dynamics of the active site and cofactor binding pocket. Importantly, we show that the flanking sequence preferences of DNMT1 highly correlate with genomic methylation in human and mouse cells, and 5-azacytidine triggered DNA demethylation is more pronounced at CpG sites with flanks disfavored by DNMT1. Overall, our findings uncover the intricate interplay between CpG-flanking sequence, DNMT1-mediated base flipping and the dynamic landscape of DNA methylation. Nature Publishing Group UK 2020-07-24 /pmc/articles/PMC7381644/ /pubmed/32709850 http://dx.doi.org/10.1038/s41467-020-17531-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Adam, Sabrina
Anteneh, Hiwot
Hornisch, Maximilian
Wagner, Vincent
Lu, Jiuwei
Radde, Nicole E.
Bashtrykov, Pavel
Song, Jikui
Jeltsch, Albert
DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
title DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
title_full DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
title_fullStr DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
title_full_unstemmed DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
title_short DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
title_sort dna sequence-dependent activity and base flipping mechanisms of dnmt1 regulate genome-wide dna methylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381644/
https://www.ncbi.nlm.nih.gov/pubmed/32709850
http://dx.doi.org/10.1038/s41467-020-17531-8
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