The Role of PRPS1 5' uORF in Translational Regulation?

Abstract

By Khan Tran, Medical Sciences

Advisor: Tom Cunningham

Presentation ID: PM_D37

Abstract: Deregulated cellular metabolism that drives growth and proliferation plays an important role in cancer development and other diseases. Phosphoribosyl pyrophosphate synthetase enzymes (PRPS1 and PRPS2) are the chief enzymes responsible for controlling the rate of cellular nucleotide biosynthesis. Therefore, both superactivating mutations that lead to increased activity as well as hypomorphic mutations that impair its activity can cause disease, suggesting that tight regulation of this key node in metabolism is necessary. We have identified an upstream open reading frame (uORF) within the 5' untranslated region (UTR) of the PRPS1 mRNA. Upstream open reading frames (uORFs) are open reading frames present within the 5' untranslated regions (5'UTRs) of a subset of mRNAs can potentially affect translation of the downstream regions - most frequently acting to suppress translation initiated from the canonical ORF. This ongoing project aims to determine the lowering effect of PRPS1 5'uORF on the translation from the translation start site, which can potentially suppress nucleotide production. Employing CRISPR-Cas9 genome-editing methodologies, we aim to generate mutations in the uORF-encoding region of the PRPS1 gene that allow us to assess the role of uORF-mediated translational control of PRPS1 protein levels. This specificity provides a therapeutic window of opportunity to inhibit nucleotide production exclusively in cancer cells.