Transcription factors (TFs) are one of the largest classes of human proteins, stemming from over 2000 protein encoding genes. Extracellular signals activate or repress TF pathways, ultimately resulting in changes to TF-DNA occupancy and concomitant gene expression. Consequently, chemical probes that offer spatial and temporal regulation over TF-DNA bindingare powerful tools for characterizing gene expression. Out of the many TF classes,the NF-κB family aremaster-regulators of the cellular inflammatory response and are implicated in a variety of cancers. The dynamics of NF-κB signaling are poorly understood, thus creating a need for the development of new chemical tools to elucidate its function. The Harki lab has recently reported a new class of TF-targeting DNA decoys for the study of NF-κB-DNA binding. These NF-κB-targetedCatch and Release DNA Decoys (CRDDs) utilize single-photon UV-irradiation to cleave the anomeric bond, leading to depurination between the sugar and nucleobase to achieve dissociation of the NF-κB-CRDD complex. Here, the toolbox of CRDD nucleotides was expanded with the development of novel nitro-functionalized pyrimidine mimics that can photochemically depurinate similarly to indole predecessors. This poster will report nucleoside synthesis, mechanistic studies of depurination, and the stabilities of CRDDs containing next-generation nucleotides.

Next generation catch and release DNA decoys with photochemically responsive pyrimidine mimics

2019 Fall National Meeting

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