|Lab Interest||Core Facility||Publication||Ciliate Links|
We are addressing questions relating to
the structure, organization and expression of genetic information. We use a
number of different biological systems in these studies including unicellular
eukaryotic organisms (the ciliated protozoan Tetrahymena thermophila, the
budding yeast Saccharomyces cerevisiae, and the pathogenic fungus Candida
albicans), as well as mammalian meiotic cells. We use a variety of
molecular, genetic, and biochemical approaches in these studies and collaborate
with structural biologists to use X-ray crystallography, mass spectrometry, and
nuclear magnetic resonance spectroscopy (NMR) to address structural questions.
Some questions we are addressing are:
Gene Reorganization During Nuclear Development
The ciliated protozoa are a rich source
of developmentally programmed gene reorganization
events. Because of the unique biology of ciliates such as Tetrahymena, we can study these events in synchronous populations using genetic, biochemical, and molecular approaches. We have described a number of such developmentally regulated events and are presently carrying out experiments designed to address questions of the mechanisms and functional significance of these rearrangements. Molecular evolution - We have used the gene encoding the glycolytic enzyme phosphoglycerate kinase (PGK) in broad, protein based phylogenetic analyses as well as in establishing a detailed phylogeny of the very diverse and interesting ciliate phylum. We have also studied the phylogeny of the origin of the "non-universal" genetic code in the ciliates and will pursue these studies in order to address very interesting questions about the origin and evolution of the genetic code.
Regulation of Gene Expression
These studies once again use
aspects of the unique biology and the ease of molecular and genetic
manipulation of ciliated protozoa, particularly Tetrahymena and Paramecium . Present studies with Tetrahymena are focussed on the transcription and processing of rRNA as well as on the structure, function, and biogenesis of the nucleolus. Using Paramecium, we are studying the processing of a homogeneous and virtually unique class of very small pre-mRNA introns.
Design and Testing of Novel Anticancer, Antiviral and Antifungal Chemotherapeutic Agents
We have targeted the essential enzyme
dUTPase for the development of specific inhibitors which may prove to be novel
and important chemotherapeutic agents. We have developed a simple screen using
S. cerevisiae to test specificity and effectiveness of inhibitors. We will carry
out structure/function studies with dUTPases from human and C. albicans. These
data will be used in computer modelling experiments to design potential specific
inhibitors for synthesis and testing.
Structure/Function Relationships with the Synaptonemal Complex
With Dr. P. Moens, we are studying both DNA and proteins of the synaptonemal complex, a structure present at pachytene of meiotic prophase and important in meiotic functions such as synapsis and recombination. We use molecular approaches to isolate and characterize DNA associated with the synaptonemal complex and to clone genes encoding proteins of the complex. Focus of present work is to use genetic and molecular techniques such as antisense technology and constructing dominant negative mutants to address questions about specific functions of synaptonemal complex proteins.