CAREER: Experimental & Computational Studies of Ancient Sm-based RNA Assemblies

University Of Virginia Main Campus, Charlottesville VA

Investigators

Abstract

Intellectual Merit: The biological information that defines an organism is stored in its genetic material (DNA), which must be converted into myriad proteins to assemble a live, functioning cell. Many molecular steps are involved in going from DNA to protein, with the biomolecule RNA playing a central role. Indeed, RNA is now thought to be the ancestral molecule at the dawn of life, as it can both store information (like DNA) and act as chemical catalyst (like protein enzymes). A remarkable, evolutionarily conserved family of Sm proteins plays key roles in RNA processing, in organisms ranging from humans to ancient single-celled organisms from the Archaeal branch of life. Sm-mediated pathways vary in scope from mRNA splicing in eukaryotes to RNA-regulated inter-cellular communication networks in bacteria. In each of these pathways at least one key step is mediated by a molecular assembly built upon Sm proteins. Given the ubiquity of the Sm family in contemporary RNA biology, ancient Sm proteins may have played a role in the pivotal transition from an ancestral RNA World to the ribonucleoprotein (RNP) world of modern life. This NSF project focuses on Sm systems from deep-branching archaeal and bacterial species. Leveraging both experiment (biochemistry, proteomics, crystallography) and computation (bioinformatics, simulations), the project will explore what ancient Sm-based RNP complexes look like (structure), their assembly pathways and dynamical behavior (function), and the interrelationships amongst the many Sm systems and their RNA partners (evolution). The work will help discover how the Sm family evolved into a pervasive scaffold for the construction of RNA-based molecular machines. The project's long-term objective - to decipher the biochemical roles of Sm proteins in the early evolution of RNA-associated molecular machines - also will illuminate, in molecular detail, the potential roles of the ancient Sm family in facilitating the transition from a primordial RNA world to our modern RNP world. Broader Impacts: Beyond its scientific impact, this project will educate and train over a dozen under-graduate and graduate students in primary research. Because the project overlaps several disciplines, including biology (RNA, evolution), chemistry (crystallography, molecular simulations) and computer science (bioinformatics), students will learn the biological sciences in a truly integrated and interdisciplinary manner: The driving questions are biological, while the tools and approaches are physical/quantitative. This same multidisciplinary approach, uniting biology and computation, is the basis for the project's central educational plan, dubbed UVaCompBio. The basic model of the UVaCompBio project is that undergraduates from the biosciences and the quantitative sciences (physics, chemistry, CS, etc.) will be paired into teams that work together on active learning exercises and mini-projects over the course of an academic term, and in several areas of computational biology (physics- and informatics-based). This effort will (i) prepare students from the biosciences for quantitative biology, and (ii) give undergraduates from the quantitative sciences a working appreciation of the fascinating nature of complex biological systems. That two-fold goal will, in turn, achieve the ultimate goal of empowering students to be fearless learners who can work at the interfaces between seemingly unrelated scientific disciplines. Thus, over the course of the project period this educational initiative will train scores of undergraduate students and, with an emphasis on quantitative biology and a minority outreach component, will simultaneously and directly address these two major goals of modern science education.