RNA-binding proteins (RBPs) make up a class of over 2,000 proteins that bind to and regulate the diverse functions of various types of RNAs, and accordingly, are involved in controlling many cellular processes. Disruption of RNA-Protein Interactions (RPIs), consequently, has been implicated in human diseases ranging from neurodegenerative and autoimmune diseases to several human cancers. Thus, targeting RBPs and RPIs has surfaced as a new frontier in RNA-targeted drug discovery which takes advantage of the endogenous regulation of messenger RNA (mRNA). This is an alternative strategy to methods currently used in the field to target transcripts which rely on anti-sense oligonucleotides (ASOs) or miRNAs, resulting in the degradation and silencing of mRNA, respectively. ASO or miRNA mediated direct targeting of RNA transcripts poses challenges and these compounds often possess issues with specificity, delivery, and tolerability. The aim of this work is to characterize the high affinity interactions of RBPs with mRNA motifs through live-cell detection using an assay previously developed for the detection of pre-miRNAs and their RBP partners, RNA-Interaction with Protein- mediated Complementation Assay (RIPCA). The goal is to be able to expand this work to allow us to study other more complex RPIs in cells composed of RNAs that are larger and more structurally diverse than pre-miRNAs and that bind proteins which perform a variety of cellular functions. Initial studies to accomplish this include representative examples of RPIs such as repeat RNAs leading to neuromuscular diseases through the dysregulation of certain RBPs or AU-rich elements within 3’UTRs of mRNA implicated in cancers. This technology provides further application towards the development of high-throughput screening to uncover inhibitors of aberrant RPIs and encourages efforts to target RNA-caused diseases through the proteins which regulate and bind to these RNA elements.

Live-cell detection and analysis of dysregulated mRNA-protein interactions using RIPCA

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ACS Fall 2022

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