Grant: Discovery Grants Program - Individual

In each living cell, large and complex machines called ribosomes synthesize all proteins. These protein factories consist themselves of two different biomolecules, namely proteins and RNAs. RNAs are nucleic acids resembling DNA, the genetic material. However in contrast to DNA, RNA can not only store information, but it has also functional roles within the cell similar to proteins. Thus, RNA is the third major biomolecule acting in our cells. The importance of RNA in carrying out crucial biochemical actions has been recognized by several recent Nobel prizes. To optimize RNA function within the ribosome, this RNA is highly modified. My proposed research focuses on the molecular mechanism of RNA modification during the early steps of ribosome formation. I will study two systems forming the most abundant RNA modification, pseudouridine. This modification is conserved in all domains of life, but the mechanism by which it occurs is not well understood. Therefore, I am using a simple bacterial model system where a single protein modifies RNA to identify the basic mechanism of pseudouridine formation. Second, I will investigate a more complex, archaeal system where ribonucleoproteins consisting of both RNA and proteins form pseudouridines. These ribonucleoproteins are also involved in the early steps of ribosome biogenesis in humans. Notably, the core protein of these ribonucleoproteins is related to the bacterial protein we are studying, thus allowing us incisive comparisons of the two systems. My aim is to determine the slowest step in the overall reaction using state-of-the-art biophysical techniques. This will be a major accomplishment in determining the mechanism of this important RNA modification. Later, my research will elucidate the chemistry of RNA modification and its specificity within the cell. The projects on RNA modification proposed here are the first step towards my long-term goal to shed light on the essential cellular process of ribosome formation, one of life's most important enzymes. Knowledge of how the cell builds macromolecular machines is useful to construct artificial nanobiomachines.