Translational regulation by covalent modification of mRNA

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Translational regulation by covalent modification of mRNA Project Summary Aging is a complex process that involves time-dependent loss of cellular functions resulting from genomic and epigenetic instability, translational dysregulation, and altered intercellular communication. Increased longevity and healthier lifespan can be promoted by altering expression of degradation- related proteins, transcription factors, chaperones, and signaling molecules in cellular systems and mouse models. For many compelling interventions, mitigating aging-related diseases in humans will involve (i) upregulation of gene expression and/or (ii) inhibition of hard-to-drug or "undruggable" proteins and ligands. Increasing protein cellular activity using small molecules and modulating the expression of non-conventional targets are compelling unmet challenges in drug discovery. In exploratory work in cells, we have consistently observed significant increases in reporter protein activity in the presence of ligands that bind to and covalently react with a specific messenger RNA (mRNA). Selective increases in protein expression by covalent modifications of mRNA would be a foundational advance for the fields of anti-aging and RNA-targeted therapeutics. The developmental studies we propose will also reveal fundamental mechanisms by which mRNA modifications in cells modulate translation. We will explore this unanticipated and intriguing aspect of protein expression, and its potential longer-term applications to aging, via the following two Aims: Through Aim 1, we will optimize the translational effect of small molecule-mediated mRNA alkylation, and, through Aim 2, we will establish the mechanism through which alkylation of an mRNA by a small molecule upregulates expression of the encoded protein.