Platinum compounds, used worldwide in chemotherapeutic regimes, bind and crosslink nucleic acids. Despite decades of use, specific in vivo DNA and RNA targets of Pt compounds are not well-described. Recognizing the potential of Pt compounds as in vivo structural tools for cellular RNAs, we have investigated Pt accumulation on RNAs following treatment with cisplatin, finding significant platination of yeast ribosomal RNA and specificity towards high-impact sites. To further identify, isolate, and visualize such targets we have modified platinum compounds for post-treatment ‘click’ azide-alkyne cycloaddition reactions. Post-treatment fluorescent labeling of ribosomal and tRNA extracted from <i>S. cerevisiae</i> treated with click-ready Pt compounds demonstrates utility of these compounds for <i>in vivo</i> exploration. Recent post-treatment fluorescent labeling in mammalian cell culture shows distinct accumulation of Pt compounds in the nucleolus, potentially linking antitumor activity to defects in ribosome assembly. Progress on comprehensive high-throughput identification of Pt-RNA and DNA cellular adducts using these new reagents will be presented.

RNA and DNA targets of platinum anticancer compounds detected using click chemistry

251st National Meeting (2016)

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