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Presented By: Department of Chemistry

Molecular consequences of deregulated rRNA processing and modification in biology and disease

Homa Ghalei (Emory University School of Medicine)

Ribosome biogenesis in eukaryotes is a complex and highly regulated process involving the action of over 200 assembly factors, bringing together a total of 79 proteins and 4 ribosomal RNAs in yeast. The maturation of rRNAs from precursor transcripts is a critical aspect of ribosome biogenesis involving the precise processing steps facilitated by essential nucleases, among which the RNA exosome complex plays a pivotal role. Additionally, over a hundred RNA chemical modifications, the majority of which are guided by small nucleolar RNAs, are deposited on the rRNAs co- and post-transcriptionally. Despite tight regulatory steps, rRNA processing and modifications go awry in several human diseases. Missense mutations in genes encoding structural subunits of the RNA exosome cause a growing family of diseases with diverse pathologies, collectively termed RNA exosomopathies. Similarly, pathogenic mutations that impact rRNA modifications are associated with neurodevelopmental disorders and implicated in the onset and progression of cancer. I will highlight our recent findings that shed light on the molecular consequences of dysregulated rRNA processing and rRNA modifications. These molecular defects have a profound impact on both the quantity and quality of ribosomes within the translating pool, thereby disrupting cellular protein homeostasis. Our results underscore the intricate interplay between ribosome biogenesis, RNA processing, modifications, and disease pathogenesis, providing new insights and a deeper understanding of these complex cellular processes.

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