The goal of our research is to understand how mobile elements (i.e., segments of DNA) move within cells and between cells. This is important because it is one of the main ways that some organisms can change their genetic makeup to respond to external stress. It is also the way that some viruses infect cells and that antibiotic resistance genes are moved between bacterial populations.
The current focus of the lab is to understand the molecular details of how certain macromolecules and their complexes work. To function properly, cells must coordinate and choreograph a large number of simultaneous events and processes. These are carried out by macromolecules such as proteins. We use x-ray crystallography as our main tool to study the fine details of how the activity and function of protein-protein and protein-DNA complexes are regulated. We employ this approach, as it is one of the few experimental techniques that produces high-resolution “snapshots” to visualize subtle changes in protein structure that often accompany functional regulation. With these snapshots in hand, we use a variety of biochemical, biophysical, and simulation approaches to bridge the structures and biological function. In particular, we are investigating how the movement of mobile genetic elements, such as transposons,is controlled. One of our current areas of emphasis is on the mechanisms of a variety of eukaryotic and procaryotic mobile elements. We also work on the Rep protein of adeno-associated virus (AAV). This protein catalyzes the integration of the AAV genome into a specific locus in human chromosome 19, making it an extremely useful tool for gene therapy studies. For more information, see my group on the Structural Biology Section home page.
Applying our Research
A detailed understanding of the workings of biological molecules is necessary if one wants to understand how they function. This knowledge is indispensable if the goal is to interfere with their action, such as to inhibit them by designing drug molecules that bind to them. For example, once we understand how the DNA-encoding antibiotic resistance genesareexchanged between bacteria, we can more rationally devise methods to prevent this process. Such knowledge is also important if one wants to use these molecular systems as tools. A variety of DNA transposons are currently being applied, both in medicine and in biotechnology. We hope that the detailed information we obtain on these systems can improve these tools.