A6 - RNA structure-function dynamics in transcript-specific translation by the ribosome

Regulation of gene expression, the decision of which proteins to make from an identical genome, is essential to specify cell types and tissues. How such regulation is executed on a gene-by-gene basis and what the decisive molecular and regulatory RNA structures are, is our major interest. The ribosome has recently emerged as an active regulator of gene expression. Not all ribosomes are identical in composition, and they do not translate all mRNAs equally: “Specialized” ribosomes preferentially translate certain transcripts to diversify gene expression. It is poorly understood how ribosome components i.e., proteins and ribosomal RNA (rRNA), mediate specificity. So far, there has been a focus on assigning roles in translation to ribosome-bound proteins. The regulatory capacity of rRNA has long remained unexplored. Ribosomes have dramatically increased in size across eukaryotic evolution, in part due to less conserved sequence “tentacle”-like insertions called rRNA expansion segments (ESs) that “expand” rRNA on the outer ribosome shell. Given this diversity of rRNA ESs, they have been overlooked for decades as tolerated mutations at non-essential domains, with largely unknown functions. rRNA ESs neither contribute to nor interfere with rRNA’s essential role in peptide-bond formation, so why do they exist? And what do they do? My postdoc work revealed a new layer of gene regulation by rRNA itself, by which exposed rRNA expansion segments directly bind to selective transcripts to control mRNA-specific translation. Our findings transform our view of one of life’s most ancient molecular machines into a dynamic regulator of gene expression. In this project, we will study the dynamic mRNA-rRNA complexes, particularly the interactions of regulatory RNA elements with the ribosome, by which selective mRNA translation by rRNA expansion segments occurs in cells. We will combine multidisciplinary expertise in intricate RNA biochemistry and genetic engineering in mouse and yeast cells with innovative RNA technology development. Structural analyses will expand our knowledge of the detailed structural and dynamic changes of mRNAs tethered to ribosomes during translation processes. This research will decipher how rRNA-directed specialized translation shapes gene expression by utilizing dynamic rRNA-mRNA complexes, which will lead us to understand the role of rRNA ESs inside cells.