Dissecting the Mechanisms of Regulation and Quality Control in Ribosome Assembly and the Consequences of their Failure

Vanderbilt University, Nashville TN

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Abstract

ABSTRACT Ribosomes carry out protein synthesis in all cells, interpreting the information contained in the mRNA to produce the proper amount of the correct protein. In addition, ribosomes also mediate mRNA quality control. Thus, misassembled, or damaged ribosomes as well as insufficient ribosome numbers can affect the sequence and abundance of proteins and mRNAs, thereby disrupting protein homeostasis. This can lead to a number of diseases, demonstrating the importance of ensuring ribosomes are accurately assembled, and produced in the correct numbers. Using a combination of biochemical, genetic, genomic, and structural tools, we will (i) investigate mechanisms that enable ribosome production by avoiding RNA folding traps and dead-end intermediates, (ii) dissect quality control pathways to identify misassembled intermediates, (iii) study how defective ribosomes are identified for repair or degradation, and (iv) explore how ribosomes are remodeled to alter translation. In the first part, we will build on work in the current funding period to study the role of ordered helix formation and snoRNA binding for rRNA folding. This work has implications for the larger field of RNA folding, and RNP assembly, as well as the ribosome heterogeneity community, which is focused on snoRNA-mediated modifications. Our work indicates that snoRNA deletions affect ribosome assembly, which must be broadly considered in the study of ribosome heterogeneity. In the second component, we will extend our work on quality control to investigate a possible proofreading mechanism that quality checks the formation of the key functional feature of the small ribosomal subunit, the decoding site. In the third area, we will study the mechanisms of ribosome repair and degradation to decipher how cells make decisions about different outcomes from one complex, collided disomes. In the last section, we will study how the ubiquitin proteasome system is linked to ribosome remodeling via degradation of released RPs, and then dissect additional biological roles for these remodeled ribosomes. Together, the proposed work will provide a comprehensive picture of ribosome homeostasis, which underpins protein homeostasis and is thus critically important to prevent human diseases including cancer and neurodegeneration.