Links between rRNA and tRNA modifications, codon use, translation, and metabolism in cancer cells

Project Summary Post-transcriptional RNA modifications are a ubiquitous feature of the stable RNAs of the translation apparatus, with attributed functions including biogenesis, stabilization of rRNA structure, and promoting the fidelity of translation. There is recent mounting evidence that rRNA and tRNA modifications play an important role as a second layer of the genetic code, tuning gene expression in response to cellular cues, and in particular altered modification states have been implicated in many types of cancers. This proposal seeks to understand the fundamental biology of rRNA and tRNA modifications as they contribute to altered gene expression supporting tumorigenesis, exploring a critical link between modifications and methionine metabolism. The overall goal of this work will be to identify correlations in modification state of the translation apparatus with changes in codon occupancy and translation rate, and to map these correlations across cancer cell lines to uncover the key link to methionine starvation. These data will offer further insights into how methionine starvation might mediate or limit cancer cell growth, informing ongoing efforts to target this pathway therapeutically. There is certain to be a fundamental relationship between the availability of methyl groups for RNA modification and gene expression patterns, and the work outlined in this proposal will serve as a strong foundation for subsequent studies on the roles of the many other types of modifications in altered programs of gene expression.