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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Veröffentlicht in:PloS one 2020-12, Vol.15 (12), p.e0243905
Hauptverfasser: Finn, Paul B, Bhimsaria, Devesh, Ali, Asfa, Eguchi, Asuka, Ansari, Aseem Z, Dervan, Peter B
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container_issue 12
container_start_page e0243905
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creator Finn, Paul B
Bhimsaria, Devesh
Ali, Asfa
Eguchi, Asuka
Ansari, Aseem Z
Dervan, Peter B
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.
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subjects Amino acids
Antifungal agents
Binding
Biology and Life Sciences
Cell cycle
Chemical engineering
Chemistry
Chromatin
Crosslinking
Deoxyribonucleic acid
DNA
DNA binding proteins
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - genetics
Gene loci
Gene sequencing
Genetic aspects
Genome, Human - drug effects
Genomes
Humans
Imidazole
Imidazoles - pharmacology
Mass spectrometry
Nucleic Acid Conformation - drug effects
Nucleotide sequence
Nylons - pharmacology
Physical Sciences
Physiological aspects
Polyamide resins
Polyamides
Polyethylene glycol
Proteins
Pyrrole
Pyrroles - pharmacology
Research and Analysis Methods
Scientific imaging
Transcription
Transcription factors
title Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome
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