Jeff Vargason's Research

Jeff Vargason's Research Interests

My research interests focus on understanding protein-nucleic acid interactions specifically in the context of RNA silencing suppression. RNA silencing (or RNA interference, RNAi) is a recently found biological process in animals, plants and fungi that shows great promise as a tool to fight disease. It is well established that genes encoded by DNA are copied into RNA, the messenger RNA (mRNA) in turn is used as a copy of the DNA blueprint to construct a protein. RNA silencing interferes with the production of the encoded protein by destroying these messenger RNAs, thereby turning off the gene preventing its encoded from being produced (or expressed). This switch mechanism is now being used to turn off genes in organisms that are used as models for humans in experimental work to understand the function of the encoded protein. In addition, there is hope that this mechanism can be used to turn off disease causing or viral genes in humans.

RNA silencing was initially discovered in plants and has been shown to facilitate the plant's recovery from viral infection. These particular plant viruses carry their genetic material in the form of RNA rather than DNA, thereby eliminating the need to copy the DNA blueprint for protein production. This RNA triggers the plant's RNA silencing process and the viral RNA is destroyed. Unfortunately, viruses have adapted diverse mechanisms to evade and suppress the antiviral defense of RNA silencing. Many viruses encode proteins for the purpose of suppressing RNA silencing at various steps in the process. The protein-RNA complex shown is the viral p19 protein from the plant hosted Carnation Italian ringspot virus bound to a small interfering RNA (siRNA). This structure was solved with x-ray crystallography during my post-doctoral research.

The long-term goal of my research will be to understand the different mechanisms by which these viral suppressor proteins bind and select for specific RNA. In addition to gaining further understanding of the RNA silencing process, the studied proteins may be useful as tools to suppress the mechanism in other organisms. The primary role of RNA silencing in humans is thought to be in the regulation of human growth and development by turning genes on at distinct stages in the life cycle. The characterization of suppressor proteins could help us to identify those genes and facilitate our understanding of human development. At least one previously characterized plant viral suppressor protein is now being used as a tool to suppress RNA silencing in mammalian cells. The major techniques used in the lab to answer these questions include: protein production via bacterial over-expression and purification; binding studies using fluorescence spectroscopy and gel mobility shift assays; and structural studies using x-ray crystallography and NMR spectroscopy.