Nad+Synthesis, Mono(ADP-Ribosyl)ation, Protein Translation, and Proteostasis in Ovarian Cancer

Abstract

The fundamental importance of ribosomes to cellular functions and broader biological outcomes is, by now, readily apparent. Recent studies have shown that the central components of the ribosome, including the repertoire of ribosomal proteins (RPs), can be regulated and diversified to control protein translation. This regulation is mediated, in part, by post-translational modifications (PTMs) of ribosomal proteins. PTMs of ribosomal proteins are versatile, may have functional consequences for translational control, and are intimately linked to human disease. In preliminary studies, we have shown that ribosome mono(ADP-ribosyl)ation (MARylation), a PTM of proteins, is dependent on the cytosolic NAD+ synthase, NMNAT-2, and the PARP monoenzyme, PARP-16, an endoplasmic-reticulum-anchored, cytosol-facing protein. In addition, our preliminary results exploring this biology have revealed that MARylation of RPs byNMNAT-2 and PARP-16: (1) attenuates protein translation and reduces protein aggregation; (2) controls loading of mRNAs onto polysomes; and (3) supports the viability of cells by promoting proteostasis. The results suggest a functional link between NAD+ production and consumption in ribosome activity. Our results suggest a model in which ribosome MARylation regulates protein synthesis to prevent protein aggregation and proteotoxic stress. In the context of ovarian cancer cells, this enhances cell growth and likely accounts for the elevated expression ofNMNAT-2. Given the important roles of PTMs on RPs in ribosome function, as well as the important role that regulation of protein translation has in maintaining proteostasis, we hypothesize that (1) NAD+-dependent, site-specific MARylation of RPs mediated by NMNAT-2 and PARP-16 affects the assembly and function of ribosomes and (2) alterations in ribosome assembly and function by MARylation of RPs is tied to cytosolic NAD+ metabolism, and affects cellular functions and viability.

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Document Details

Document Type
Technical Report
Publication Date
Oct 01, 2022
Accession Number
AD1194089

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  • W. L. Kraus

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  • University of Texas at Dallas

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