Control of cancer-related transcription factor's binding to DNA

Beibei Liu, James K Bashkin, Gregory M K Poon, Shuo Wang, Siming Wang, W David Wilson

Overview

A remarkable complex of double-stranded DNA, PU.1 protein, and a pyrrole-imidazole polyamide is described. PU.1 is implicated in many cancers and the ability to control its DNA binding is important. Inhibitors of PU.1-DNA binding are also described.

Summary

PU.1. is often referred to as an undruggable target, but we describe numerous inhibitors that prevent it from binding to DNA and remove bound PU.1 from DNA. We also describe a ternary complex of DNA, PU.1, and a pyrrole-imidazole polyamide that is stabilized by the formation of the ternary complex.

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Author Comments

Dr. James Bashkin, D. Phil.
Dr. James Bashkin, D. Phil.
University of Missouri-St. Louis
Professor
Bioorganic chemistry, nucleic acids, HPV, antivirals
St. Louis, MO | United States
This is an exciting collaboration among three groups, depending on the PU.1 expertise of Gregory Poon, the biophysics expertise and measurements of W. David Wilson and his group, and the synthetic chemistry of James Bashkin. Both Poon and Wilson are from Georgia State University while Bashkin is from the University of Missouri-St. Louis.Dr. James Bashkin, D. Phil.

Resources

Modulating DNA by polyamides to regulate transcription factor PU.1-DNA binding interactions.

Authors:
Dr. James Bashkin, D. Phil.
Dr. James Bashkin, D. Phil.
University of Missouri-St. Louis
Professor
Bioorganic chemistry, nucleic acids, HPV, antivirals
St. Louis, MO | United States

Biochimie 2019 Dec 21;167:1-11. Epub 2019 Aug 21.

Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA. Electronic address:

Hairpin polyamides are synthetic small molecules that bind DNA minor groove sequence-selectively and, in many sequences, induce widening of the minor groove and compression of the major groove. The structural distortion of DNA caused by polyamides has enhanced our understanding of the regulation of DNA-binding proteins via polyamides. Polyamides have DNA binding affinities that are comparable to those proteins, therefore, can potentially be used as therapeutic agents to treat diseases caused by aberrant gene expression. In fact, many diseases are characterized by over- or under-expressed genes. PU.1 is a transcription factor that regulates many immune system genes. Aberrant expression of PU.1 has been associated with the development of acute myeloid leukemia (AML). We have, therefore, designed and synthesized ten hairpin polyamides to investigate their capacity in controlling the PU.1-DNA interaction. Our results showed that nine of the polyamides disrupt PU.1-DNA binding and the inhibition capacity strongly correlates with binding affinity. One molecule, FH1024, was observed forming a FH1024-PU.1-DNA ternary complex instead of inhibiting PU.1-DNA binding. This is the first report of a small molecule that is potentially a weak agonist that recruits PU.1 to DNA. This finding sheds light on the design of polyamides that exhibit novel regulatory mechanisms on protein-DNA binding.

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Source
http://dx.doi.org/10.1016/j.biochi.2019.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883780PMC
December 2019
4 Reads
3.362 Impact Factor

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