Beyond Modification: Defining Hidden Roles of snoRNPs in Ribosome Assembly

forthcoming

The assembly of new ribosomes is a conserved and tightly regulated process required for the growth of all living beings. Successful ribosome production requires the coordinated action of hundreds of cellular factors, including small nucleolar ribonucleoprotein particles (snoRNPs). Human snoRNP defects or alterations in snoRNP expression are linked to bone marrow disorders, neurodegeneration, and cancer. We recently discovered that a specialized class of snoRNPs play central yet underappreciated roles in orchestrating the earliest events of ribosome assembly, beyond their well-known function of directing rRNA modification. These specialized snoRNPs, which we termed assembly-promoting (ap-)snoRNPs, possess unique RNA and protein components that we hypothesize empower each snoRNP to guide a specific step of ribosome assembly, thereby ensuring that new ribosomes are properly made. Their constituents, 3D structures, dynamics and mechanism of action are virtually unknown. This synergistic research consortium will define the functions of this newly discovered class of snoRNPs by integrating recent advances in genetics, high-throughput RNA biochemistry, cryo-electron microscopy and single molecule biophysics. The goals of this research project are to inventory yeast and human ap-snoRNPs that act in ribosome assembly, determine their components and 3D structures, define their biological functions, and unravel the physical mechanisms by which they promote ribosome assembly. Highly complementary approaches and a broad program of discovery will mitigate the risks associated with this challenge. The results of this collaborative research are expected to change the current view of snoRNP function and provide a comprehensive platform for understanding how snoRNPs promote ribosome assembly and how snoRNP deficiencies contribute to human disease.