Abstract 2429 Disease-associated variants of the structural subunits of RNA exosome complex cause distinct translation defects

The RNA exosome is an evolutionarily conserved ribonuclease complex required for processing and degradation of many cellular coding and non-coding RNAs, including ribosomal RNA (rRNA). The multi-subunit RNA exosome consists of a 3-subunit cap, a 6-subunit barrel-like core, and a catalytically active base. Missense mutations in genes encoding several structural subunits of the RNA exosome have been linked to human diseases, collectively termed "RNA exosomopathies". Symptoms of these diseases vary amongst patients and range from neurological defects to developmental disorders. Using biochemical approaches, here, we compare the impact of four disease-causing missense variants in two cap exosome subunits (Rrp4 and Rrp40) and two core exosome subunits (Rrp41 and Rrp46), modeled in the budding yeast, S. cerevisiae, on ribosome biogenesis and translation. Our results show that all four variants cause rRNA processing defects and an overall significant decrease in translation. However, translation is perturbed in distinct ways in cap vs core subunit variants. Our findings suggest that different RNA exosomopathy mutations can result in in vivo consequences that are both unique and shared amongst the variants and could provide new insights into the molecular defects underlying each distinct pathology. This work was supported by NIH awards R35GM138123 to H.G, R01GM130147 to A.H.C and Ambro van Hoof and a Synergy II Nexus Award provided by the Woodruff Health Sciences Center (WHSC), Emory School of Medicine, the Office of the Provost, and Emory College of Arts and Sciences (ECAS) to H.G. and A.H.C. L.A.C. was supported by NIH T32GM149422.