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Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides
In the cell, DNA is arranged into highly-organised and topologically-constrained (supercoiled) structures. It remains unclear how this supercoiling affects the detailed double-helical structure of DNA, largely because of limitations in spatial resolution of the available biophysical tools. Here, we...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887228/ https://www.ncbi.nlm.nih.gov/pubmed/33594049 http://dx.doi.org/10.1038/s41467-021-21243-y |
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author | Pyne, Alice L. B. Noy, Agnes Main, Kavit H. S. Velasco-Berrelleza, Victor Piperakis, Michael M. Mitchenall, Lesley A. Cugliandolo, Fiorella M. Beton, Joseph G. Stevenson, Clare E. M. Hoogenboom, Bart W. Bates, Andrew D. Maxwell, Anthony Harris, Sarah A. |
author_facet | Pyne, Alice L. B. Noy, Agnes Main, Kavit H. S. Velasco-Berrelleza, Victor Piperakis, Michael M. Mitchenall, Lesley A. Cugliandolo, Fiorella M. Beton, Joseph G. Stevenson, Clare E. M. Hoogenboom, Bart W. Bates, Andrew D. Maxwell, Anthony Harris, Sarah A. |
author_sort | Pyne, Alice L. B. |
collection | PubMed |
description | In the cell, DNA is arranged into highly-organised and topologically-constrained (supercoiled) structures. It remains unclear how this supercoiling affects the detailed double-helical structure of DNA, largely because of limitations in spatial resolution of the available biophysical tools. Here, we overcome these limitations, by a combination of atomic force microscopy (AFM) and atomistic molecular dynamics (MD) simulations, to resolve structures of negatively-supercoiled DNA minicircles at base-pair resolution. We observe that negative superhelical stress induces local variation in the canonical B-form DNA structure by introducing kinks and defects that affect global minicircle structure and flexibility. We probe how these local and global conformational changes affect DNA interactions through the binding of triplex-forming oligonucleotides to DNA minicircles. We show that the energetics of triplex formation is governed by a delicate balance between electrostatics and bonding interactions. Our results provide mechanistic insight into how DNA supercoiling can affect molecular recognition, that may have broader implications for DNA interactions with other molecular species. |
format | Online Article Text |
id | pubmed-7887228 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78872282021-03-03 Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides Pyne, Alice L. B. Noy, Agnes Main, Kavit H. S. Velasco-Berrelleza, Victor Piperakis, Michael M. Mitchenall, Lesley A. Cugliandolo, Fiorella M. Beton, Joseph G. Stevenson, Clare E. M. Hoogenboom, Bart W. Bates, Andrew D. Maxwell, Anthony Harris, Sarah A. Nat Commun Article In the cell, DNA is arranged into highly-organised and topologically-constrained (supercoiled) structures. It remains unclear how this supercoiling affects the detailed double-helical structure of DNA, largely because of limitations in spatial resolution of the available biophysical tools. Here, we overcome these limitations, by a combination of atomic force microscopy (AFM) and atomistic molecular dynamics (MD) simulations, to resolve structures of negatively-supercoiled DNA minicircles at base-pair resolution. We observe that negative superhelical stress induces local variation in the canonical B-form DNA structure by introducing kinks and defects that affect global minicircle structure and flexibility. We probe how these local and global conformational changes affect DNA interactions through the binding of triplex-forming oligonucleotides to DNA minicircles. We show that the energetics of triplex formation is governed by a delicate balance between electrostatics and bonding interactions. Our results provide mechanistic insight into how DNA supercoiling can affect molecular recognition, that may have broader implications for DNA interactions with other molecular species. Nature Publishing Group UK 2021-02-16 /pmc/articles/PMC7887228/ /pubmed/33594049 http://dx.doi.org/10.1038/s41467-021-21243-y Text en © The Author(s) 2021 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 Pyne, Alice L. B. Noy, Agnes Main, Kavit H. S. Velasco-Berrelleza, Victor Piperakis, Michael M. Mitchenall, Lesley A. Cugliandolo, Fiorella M. Beton, Joseph G. Stevenson, Clare E. M. Hoogenboom, Bart W. Bates, Andrew D. Maxwell, Anthony Harris, Sarah A. Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides |
title | Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides |
title_full | Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides |
title_fullStr | Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides |
title_full_unstemmed | Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides |
title_short | Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides |
title_sort | base-pair resolution analysis of the effect of supercoiling on dna flexibility and major groove recognition by triplex-forming oligonucleotides |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887228/ https://www.ncbi.nlm.nih.gov/pubmed/33594049 http://dx.doi.org/10.1038/s41467-021-21243-y |
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