The nucleolus, a dynamic phase-separated compartment in the nucleus, is the primary site of ribosome biogenesis. Its tri-partite structure forms around the actively transcribed ribosomal DNA (rDNA) genes, which produce the key ribosomal component rRNA. Nucleolar structure changes significantly in response to different types of stress including rDNA double strand breaks, RNA Pol I transcription inhibition and defects in ribosome biogenesis also known as nucleolar stress. These disruptions trigger a cellular stress response which was shown to result in a restructuring of the human nucleolus and the formation of nucleolar caps along the nucleolar periphery, bipartite structures containing fibrillar centers and dense fibrillar centers surrounding intra-nucleolar granular components. The nucleolar restructuring into nucleolar caps is a concerted regulatory process involving the spatial reshuffling of specific nucleoplasmic and nucleolar components, depending on the type of stress, in a dynamic and energy-dependent manner. Nucleolar morphology has proven a useful diagnostic tool in cancer pathology as both hyper- and hypoactivation of rDNA transcription and loss of rDNA repeats have been linked to various cancers and tumorigenesis. However, while it has been shown that different types of nucleolar stress lead to variations in nucleolar cap formation, the mechanisms underlying nucleolar cap formation and resolution are still unknown. Using proteomics, genetic screens and biochemistry, the overarching goal of this research project is to determine the regulatory mechanisms that underly nucleolar cap formation in response to rDNA stress, the repair pathways that resolve rDNA stress, and the mechanism of re-activation of rDNA transcription following repair in human cells.

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