National Institute of Allergy and Infectious Diseases 2R01AI101057-12A1

Guide RNA Binding Complex

This NIH grant funds research on the RNA editing mechanisms in Trypanosoma brucei, focusing on RNA binding complexes and helicase function to understand and visualize the editing pathway, potentially aiding therapeutic development.

Description

Parasitic infections caused by Trypanosoma brucei spp. have historically undermined public health and economies in Sub-Saharan Africa, only partially curtailed by recently approved therapeutics. Although the long-term impact of repurposed drugs remains unclear, sustained research has positioned T. brucei among the most prolific unicellular model systems. Paradigms of antigenic variation, GPI-anchoring, RNA interference, and others have critically informed eukaryotic biology, while discoveries of RNA editing and guide RNAs (gRNAs) have translated into genome and transcriptome-altering technologies. The trypanosomal mitochondrial editosome consists of interacting RNA binding and enzymatic modalities. RNA editing substrate binding complexes (RESCs) enclose gRNAs and mRNAs, initiating editing by scaffolding their imperfect hybrid. RNA editing catalytic complexes (RECCs) recognize mismatches in the hybrid as editing sites and execute mRNA cleavage, uridine insertion or deletion, and re-ligation reactions. A principal auxiliary factor, DEAH-box RNA helicase KREH2, likely contributes to editing progression, although the mechanism remains unclear. Empowered by recent advances in cryo-electron microscopy (cryoEM), the project aims to visualize the editing pathway by determining RESC structures at discernible steps, defining functions of RESCs, and elucidating their structures through cryoEM. The project includes two aims: 1) to investigate RESCs that bind gRNA and pre-mRNA to initiate and monitor editing, and 2) to examine KREH2 helicase as the molecular motor driving editing by remodeling RESCs.

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