Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.

Pyrrole-imidazole (Py-Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current model...

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Main Authors: Paul B Finn, Devesh Bhimsaria, Asfa Ali, Asuka Eguchi, Aseem Z Ansari, Peter B Dervan
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2020-01-01
Series:PLoS ONE
Online Access:https://doi.org/10.1371/journal.pone.0243905
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spelling doaj-e69207fc8c78448ca363229f849bd1bd2021-03-04T13:00:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-011512e024390510.1371/journal.pone.0243905Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.Paul B FinnDevesh BhimsariaAsfa AliAsuka EguchiAseem Z AnsariPeter B DervanPyrrole-imidazole (Py-Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of DNA binding. Determining the impact of genomic architecture and the local chromatin landscape on polyamide-DNA sequence specificity remains an unresolved question that impedes their effective deployment in vivo. In this report we identified polyamide-DNA interaction sites across the entire genome, by covalently crosslinking and capturing these events in the nuclei of human LNCaP cells. This technique confirms the ability of two eight ring hairpin-polyamides, with similar architectures but differing at a single ring position (Py to Im), to retain in vitro specificities and display distinct genome-wide binding profiles.https://doi.org/10.1371/journal.pone.0243905
collection DOAJ
language English
format Article
sources DOAJ
author Paul B Finn
Devesh Bhimsaria
Asfa Ali
Asuka Eguchi
Aseem Z Ansari
Peter B Dervan
spellingShingle Paul B Finn
Devesh Bhimsaria
Asfa Ali
Asuka Eguchi
Aseem Z Ansari
Peter B Dervan
Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.
PLoS ONE
author_facet Paul B Finn
Devesh Bhimsaria
Asfa Ali
Asuka Eguchi
Aseem Z Ansari
Peter B Dervan
author_sort Paul B Finn
title Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.
title_short Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.
title_full Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.
title_fullStr Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.
title_full_unstemmed Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome.
title_sort single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct dna-binding profiles across the human genome.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2020-01-01
description Pyrrole-imidazole (Py-Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of DNA binding. Determining the impact of genomic architecture and the local chromatin landscape on polyamide-DNA sequence specificity remains an unresolved question that impedes their effective deployment in vivo. In this report we identified polyamide-DNA interaction sites across the entire genome, by covalently crosslinking and capturing these events in the nuclei of human LNCaP cells. This technique confirms the ability of two eight ring hairpin-polyamides, with similar architectures but differing at a single ring position (Py to Im), to retain in vitro specificities and display distinct genome-wide binding profiles.
url https://doi.org/10.1371/journal.pone.0243905
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AT deveshbhimsaria singlepositionsubstitutionofhairpinpyrroleimidazolepolyamidesimpartsdistinctdnabindingprofilesacrossthehumangenome
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