Control Mechanisms of the Holo-Editosome in Trypanosomes

Abstract

RNA metabolism in the single mitochondrion of trypanosomes and related kinetoplastid protozoa exhibits a unique posttranscriptional maturation of mRNAs by specific U insertion/deletion RNA editing that creates protein-coding sequences in 12 mRNA targets. In T. brucei, the editing apparatus includes over 40 proteins and hundreds of small noncoding guide RNAs (gRNAs). The editing machinery faces several challenges besides the need to coordinate its numerous components. These challenges include specific targeting of over 3000 sites in mRNA-gRNA hybrids, faithful discrimination of a large pool of pre-edited, partially edited intermediates and fully edited transcripts in the mitochondrial milieu, and differential control of editing in insect and mammal hosts. However, the basic mechanistic steps that control substrate loading, initiation, and progression of editing are not understood. A growing understanding of the holo-editosome organization offers important clues. The editing holoenzyme is a dynamic aggregate of multi-protein subcomplexes: the “RNA-free” editing enzyme termed RECC and auxiliary RNPs. One RNP is the REH2C subcomplex that includes an RNA helicase. Another subcomplex is RESC that includes two proposed modules: GRBC and REMC. The current model of RNA editing apparatus involves multi-RNP complexes serving as scaffolds that bring together mRNA, gRNA, and the RECC enzyme. Such molecular scaffolds may provide a context for specific mRNA-gRNA annealing, specific site recognition, and editing fidelity and progression. Here, we review protein components in RECC that exhibit differential effects during the life cycle of trypanosomes and specific components of the auxiliary RNPs that may participate in editing control. Notably, variants of RECC and the accessory RNPs have been identified. These findings lead us to propose an updated model of RNA editing, whereby isoforms of enzymatic and nonenzymatic subcomplexes establish “dynamic” functionally distinct holo-editosomes. This should expand the flexibility and specificity of the control mechanisms in RNA editing.