Modulation of NF-κB-dependent Gene Transcription Using Programmable DNA Minor Groove Binders

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2011 Dec 29

PMID 22203967

Citations 69

Authors

Jevgenij A Raskatov

Jordan L Meier

James W Puckett

Fei Yang

Parameswaran Ramakrishnan

Peter B Dervan

Affiliations

Soon will be listed here.

Abstract

Nuclear factor κB (NF-κB) is a transcription factor that regulates various aspects of immune response, cell death, and differentiation as well as cancer. In this study we introduce the Py-Im polyamide 1 that binds preferentially to the sequences 5'-WGGWWW-3' and 5'GGGWWW-3'. The compound is capable of binding to κB sites and reducing the expression of various NF-κB-driven genes including IL6 and IL8 by qRT-PCR. Chromatin immunoprecipitation experiments demonstrate a reduction of p65 occupancy within the proximal promoters of those genes. Genome-wide expression analysis by RNA-seq compares the DNA-binding polyamide with the well-characterized NF-κB inhibitor PS1145, identifies overlaps and differences in affected gene groups, and shows that both affect comparable numbers of TNF-α-inducible genes. Inhibition of NF-κB DNA binding via direct displacement of the transcription factor is a potential alternative to the existing antagonists.

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