Interference with DNA repair after ionizing radiation by a pyrrole-imidazole polyamide
Pyrrole-imidazole (Py–Im) polyamides are synthetic non-genotoxic minor groove-binding small molecules. We hypothesized that Py–Im polyamides can modulate the cellular response to ionizing radiation. Pre-treatment of cells with a Py-Im polyamide prior to exposure to ionizing radiation resulted in a delay in resolution of phosphorylated γ-H2AX foci, increase in XRCC1 foci, and reduced cellular replication potential. RNA-sequencing of cell lines exposed to the polyamide showed induction of genes related to the ultraviolet radiation response. We observed that the polyamide is almost 10-fold more toxic to a cell line deficient in DNA ligase 3 as compared to the parental cell line. Alkaline single cell gel electrophoresis reveals that the polyamide induces genomic fragmentation in the ligase 3 deficient cell line but not the corresponding parental line. The polyamide interferes directly with DNA ligation in vitro. We conclude that Py-Im polyamides may be further explored as sensitizers to genotoxic therapies.
© 2018 the Author(s). This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Received: January 22, 2018; Accepted: April 19, 2018; Published: May 1, 2018. We acknowledge the UCLA CNSI Advanced Light Microscopy/Spectroscopy Shared Resource Facility, the UCLA Center for System Biomedicine Facility. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. The sequencing data is uploaded to https://www.ncbi.nlm.nih.gov/bioproject. BioProject ID: PRJNA445611. This study was supported by Prostate Cancer Foundation Young Investigator Award to Dr Nicholas George Nickols, Stop Cancer Career Development Award to Dr Nicholas George Nickols, National Institute of General Medical Sciences grant R01GM27681 to Peter B Dervan, Jonsson Cancer Center Foundation Seed Grant to Dr Nicholas George Nickols. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: F. Yang is the vice president (research) at and has ownership interest (including patents) in Gene Sciences, Inc. N.G. Nickols has ownership interest (including patents) in Gene Sciences, Inc. P.B. Dervan is the founder of, has ownership interest (including patents) in, and is a consultant/advisory board member for Gene Sciences, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Published - 10.1371_journal.pone.0196803.pdf
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