Key factors in human ribosome biogenesis

Yale University, New Haven CT

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Abstract

? DESCRIPTION (provided by applicant): Ribosome biogenesis, beyond being a critical requirement for growth in all eukaryotic cells, has a broad impact on the etiology of numerous human disorders. Human genetic diseases caused by mutations in structural components of the ribosome or in factors required to make ribosomes in the cell nucleolus are called ribosomopathies. These largely congenital disorders present with a variety of morbidities: bone marrow failure, liver cirrhosis, pancreatic insufficiency, craniofacial dysmorphology and skin abnormalities. The pathogenesis of cancer, too, is linked to changes in nucleolar morphology and function. Because decreased nucleolar function can abrogate tumorigenicity, rRNA transcription and ribosome biogenesis have recently emerged as attractive new targets for anticancer therapies. Despite the clear impact of abnormalities in ribosome biogenesis on human disease, human ribosome biogenesis and the mechanisms behind the diverse ribosomopathies are just beginning to be investigated and elucidated. Our long-term goal is to understand how the architecture and function of the cell nucleolus relates to rare human genetic diseases and drives cancer. The objective of this application is to undertake a focused, in-depth approach to investigate the molecular basis of a putative ribosomopathy, North American Indian Childhood Cirrhosis (NAIC), and in doing so further probe how ribosomes are made in human cells. NAIC is a recessive congenital disease present in a First Nations Canadian population that maps to a R565W mutation in hUTP4/Cirhin, a protein first described in my laboratory in yeast. We propose: 1) To test the hypothesis that the mutation causative in NAIC leads to defective ribosome biogenesis in human cells; 2) To probe the mechanism by which defects in ribosome biogenesis caused by depletion or mutation of hUTP4/Cirhin lead to disease and 3) To test whether depletion or mutation of UTP4/Cirhin results in defects in organ development in vivo in the model organism, Xenopus tropicalis. These three Specific Aims are designed to pursue fundamental questions that will reveal how ribosomes are made in human cells and in an animal model through the lens of a human disease.