Monitoring mechanisms in mammalian ribosome biogenesis

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DESCRIPTION (provided by applicant): Synthesis of new ribosomes is an essential cellular activity and it is becoming increasingly clear that ribosome biogenesis plays an important role in cancer and human disease. However, molecular mechanisms of this highly complex process and its links to other cellular pathways remain inadequately understood, especially in a mammalian system. Recent evidence indicates that mammalian cells possess a surveillance system that communicates perturbations in ribosome synthesis to the tumor suppressor p53. It is currently unknown how errors in ribosome assembly are recognized and which components in the ribosome biogenesis machinery mediate signaling to the p53 pathway. We seek to understand the mechanisms that provide monitoring of ribosome biogenesis in mammalian cells through analysis of the newly discovered nucleolar GTP-binding proteins (GTPases) Nog1 and Nug1A/B. Recent experimental evidence shows that the function of these GTPases is essential for synthesis of 60S ribosomal subunits and also implicates them as potential signaling links between ribosome synthesis and proliferation control pathways. The studies proposed here are designed to elucidate the role of the mammalian nucleolar GTPases in surveillance of ribosome biogenesis and to gain insight into the molecular mechanisms of their action. We will begin by addressing two questions to assess the monitoring function of the nucleolar GTPases. What is the role of mouse Nog1 and Nug1A/B in rRNA maturation? How does their function contribute to the accuracy of ribosome biogenesis and signaling to the p53 network? By using a combination of biochemical and genetic approaches, we will further investigate the molecular mechanisms of a model representative of the group, Nog1. What role do guanine nucleotide binding and hydrolysis play in the activities of this GTPase? What proteins serve as effectors and regulators of Nog1 function and how do they influence its GTPase cycle? Collectively, these studies should provide significant new information on a novel group of GTP-binding proteins, yield mechanistic insights into ribosome assembly and contribute to our understanding of the link between ribosome biogenesis and proliferation control in mammalian cells.