Ribosome biogenesis is an essential cellular process that must meet the demands of normal cell growth and stress responses. The foundation of ribosome biogenesis is the synthesis of ribosomal RNA. In this process, ribosomal RNA is captured, chemically modified, cleaved, and released by small nucleolar ribonucleoprotein particles (snoRNPs). Studies in my laboratory over the years suggest an emerging principle in which the single act of rRNA capture by snoRNPs encompasses multiple coordinated events occurring simultaneously with catalysis at locations distal from the active site. The multi-component yet tractable H/ACA snoRNPs offer a prototypical system for examining these interactions in detail. Our goals are to establish a mechanistic view of ribosomal RNA capture and release by snoRNPs from the initial docking through the end of chemical reactions. The proposed studies will also provide an understanding of RNA-protein composite enzymes in general at atomic details. Cancerous cells display increased ribosome synthesis. Identifying signals that inhibit or promote ribosome synthesis will potentially reveal promising targets for therapy against tumor growth. The increasing evidence that 5-fluorouracil (5-FU) is incorporated into functional RNAs necessitates investigation of its role in inhibiting ribosomal RNA synthesis by blocking pseudouridylases. Human telomerase is a specialized H/ACA RNP that exploits the H/ACA RNA domain for its localization and maturation. The genetic disease dyskeratosis congenita (DC), which predisposes patients to epithelial cancers, results from mutations in telomerase RNA and two of the four core proteins in human H/ACA snoRNPs. Although defects in both ribosome biogenesis and telomere synthesis are observed in murine embryonic stem cells bearing DC mutants, a thorough understanding of how DC mutations affect the functioning of H/ACA snoRNPs will provide an understanding of the manner in which these mutations contribute to the pathology of DC.
Cancerous cells display increased rate of ribosome synthesis. Identifying signals that inhibit or promote ribosome synthesis will potentially reveal promising targets for therapy against tumor growth.
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