Chemistry and Biology of ADP-Ribosylation-Dependent Signaling

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Abstract Protein ADP-ribosylation is a complex and highly dynamic process regulated by distinct writer, reader and eraser proteins. As a key post-translational modification, protein ADP-ribosylation is catalyzed by ADP- ribosyltransferases (ARTs) by using nicotinamide adenine dinucleotide (NAD+) as a co-substrate and plays important roles in regulating a significant number of physiological and pathophysiological processes. ADP- ribosylated proteins can be recognized by reader proteins, triggering downstream signaling cascades or effector functions in direct or indirect manners. The ADP-ribosylation-mediated signaling can be modulated by eraser proteins that rapidly remove covalently attached ADP-ribose unit(s). In addition to their extensive involvements in physiological events, the writers, readers, and erasers of protein ADP-ribosylation are broadly implicated in numerous diseases. However, it remains elusive for the functions and roles of ADP-ribosylation in human health and pathogenesis of many diseases. Despite technological advancement, little information is known regarding the identity of the reader(s) and eraser(s) for individual ADP-ribosylated proteins, the preferred ADP-ribosylated protein(s) for a specific reader or eraser protein, and the ADP-ribosylation-centered interaction networks. And tools and technologies have yet to be developed for unambiguously mapping ADP-ribosylation-dependent interactome. The goal of this MIRA project is to develop novel chemical tools to address these major challenges. In next five years, we are aimed to generate novel bifunctional NAD+ molecules for unbiased and faithful dissection of ADP-ribosylation-dependent interactome and define their roles in cell signaling. Successful completion of this work will result in a set of novel and important chemical tools for addressing challenges in research on ADP-ribosylation-dependent events and processes across multiple areas. These innovative tools may lead to major breakthroughs in understanding of the cellular functions and regulatory roles of protein ADP- ribosylation in physiology and pathophysiology and in the development of novel diagnostics and therapeutics targeting ADP-ribosylation-associated activities and pathways for many human diseases.