Research

Research

RNA Biology in trypanosomes mitochondria

 

We combine approaches in molecular genetics, structural biology, biochemistry, proteomics, and bioinformatics to study the amazing RNA biology of trypanosome parasites.  One research line is on an RNA editing process by uridine insertion and deletion that creates amino acid coding triplets in most mRNAs. Yet a single error in the U-changes yields a frame-shift. Trypanosomes split from other eukaryotic lineages over a hundred million years ago, yet this editing has analogies with RNAi, CRISPR/Cas9, mRNA splicing and other systems directed by small non-coding RNAs (ncRNAs).

 

RNA editing is catalyzed by holo-editosomes that include several RNP subcomplexes with over 40 proteins, mRNAs, and hundreds of non-coding guide RNAs (gRNAs). We focus on the regulatory mechanisms of holo-editosome assembly and function. For example, we identified the first catalytic accessory mRNP (termed REH2C), which includes mRNA, the RNA Editing Helicase 2 (REH2) and an intriguing 8-zinc finger termed REH2-Associated Factor 1 (H2F1). We now reconstituted a catalytically active REH2C complex using full-length recombinant proteins. We also have a long tradition using in vitro assays with synthetic RNAs and purified editing components. Multiple collaborations add expertise in protein/RNA structure and homology modeling (Mooers lab), deep sequencing (Schnaufer lab), and proteomics (Wohlschlegel lab) to our studies of this vital process in major human parasites.

 

Development of lead compounds against trypanosomes

 

A recent new line of investigation in our lab is an exciting collaboration with Tom Meek’s lab that proposes to develop lead drugs with selective inhibitory activity against major potential targets in T. brucei and T. cruzi, the causative agents of important human diseases: African Sleeping Sickness and American Chagas Disease, respectively.  Currently, we are testing drugs developed in the Meek lab against N-ribosyl transferases, cruzain, and TbCat B. Our studies also involve molecular analysis of the relevant genes in trypanosomes.

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