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.
CITATION STYLE
Diaz-Perez, S., Kane, N., Kurmis, A. A., Yang, F., Kummer, N. T., Dervan, P. B., & Nickols, N. G. (2018). Interference with DNA repair after ionizing radiation by a pyrrole-imidazole polyamide. PLoS ONE, 13(5). https://doi.org/10.1371/journal.pone.0196803
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