Uncovering novel players in nucleolar organization and function

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PROJECT SUMMARY The nucleolus is one of the largest membraneless cellular organelles, responsible for ribosomal RNA (rRNA) transcription, rRNA processing, and ribosome assembly. Nucleolar size and number are often correlated with protein synthesis rate and proliferative capacity of a cell. Seminal studies have shown that increased nucleolar size and number are common features of many cancers and that nucleolar defects are associated with neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Nevertheless, fundamental information is still lacking on the molecular players and mechanism that control the dynamic assembly and activity of the nucleolus in health and disease. We identified a novel nucleolar protein named ZNF692 that is necessary to maintain nucleolar integrity and activity. Knocking down ZNF692 resulted in abnormal ring-like nucleolar morphology, as well as compromised protein synthesis. Our preliminary results indicate that ZNF692 interacts with multiple nucleolar proteins, including NPM1, as well as rRNA processing and ribosome assembly factors. Our hypothesis is that ZNF692 assembles a hub for ribosome biogenesis in the nucleolus by simultaneously recruiting pre-rRNA, ribosomal proteins, and ribosome biogenesis factors. We will define the molecular mechanism regulated by ZNF692 in ribosome production (Aim 1). We will define the domains of ZNF692 that regulate nucleolar integrity and activity (Aim 2). We will then determine how ZNF692 may regulate nucleolar assembly and dynamics (Aim 3). Our work has the potential to provide fundamental data on the mechanisms and key regulators of nucleolar activity and could become the basis for the development of novel approaches to alter nucleolar activity in diseased cells.