Dynamic RNA holo‐editosomes with subcomplex variants: Insights into the control of trypanosome editing

Abstract

RNA editing causes massive remodeling of the mitochondrial mRNA transcriptome in trypanosomes and related kinetoplastid protozoa. This type of editing involves the specific insertion or deletion of uridylates (U) directed by small noncoding guide RNAs (gRNAs). Because U-insertion exceeds U-deletion by a factor of 10, editing increases the nascent mRNA size by up to 55%. In Trypanosoma brucei, the editing apparatus uses ~40 proteins and >1,200 gRNAs to create the functional open reading frame in 12 mRNAs. Thousands of sites are specifically recognized in the pre-edited mRNAs and a myriad of partially edited transcript intermediates accumulates in mitochondria. The control of editing is poorly understood, but past work suggests that it occurs during substrate recognition, the initiation and progression of editing, and during the life-cycle in different hosts. The growing understanding of the editing proteins offers clues about editing control. Most editing proteins reside in the "RNA-free" RNA editing core complex (RECC) and in the accessory RNA editing substrate complex (RESC) that contains gRNA. Two accessory RNA helicases are known, including one in the RNA editing helicase 2 complex (REH2C). Both the RESC and the REH2C associate with mRNA, providing a rationale for the assembly of mRNA or its mRNPs, RESC, and the RECC enzyme. Identified variants of the canonical editing complexes further complicate the model of RNA editing. We examine specific examples of complex variants, differential effects of editing proteins on the mRNAs within and between T. brucei life stages, and possible control points in RNA holo-editosomes. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

MRB10130 is a RESC assembly factor that promotes kinetoplastid RNA editing initiation and progression

“…U-indel RNA editing involves a complex protein interaction network entailing cooperative and/or competitive binding of numerous proteins, mRNAs, and gRNAs (Hashimi et al 2013;Aphasizheva and Aphasizhev 2016;Read et al 2016;Cruz-Reyes et al 2018). RESC is a dynamic and heterogeneous complex that comprises the primary nonenzymatic component of the U-indel editing machinery in kinetoplastid mitochondria.…”

“…A novel and extreme type of RNA editing occurs in the mitochondria of kinetoplastid flagellates, entailing specific insertion and deletion of uridylate (U) residues to correct frame shifts and create translatable open reading frames (ORFs) (Hashimi et al 2013;Aphasizheva and Aphasizhev 2016;Read et al 2016;Cruz-Reyes et al 2018;Zimmer et al 2018). U insertion/deletion (U-indel) editing is essential for survival of these organisms, which include several deadly human pathogens (Stuart et al 2008), because fully edited mRNAs encode proteins involved in mitochondrial bioenergetics and translation.…”

Protein features for assembly of the RNA editing helicase 2 subcomplex (REH2C) in Trypanosome holo-editosomes

“…However, these variants differ minimally in their relative content of the canonical MRB3010 in GRBC. Additional variations in protein composition have been reported in purifications of RESC components by different labs (reviewed in [1]). Interestingly, native and genetically-induced changes in MRB3010 stoichiometry may be common.…”

“…The mRNA editing trans factors core enzyme RECC and accessory RESC and REH2C exhibit transient and stable contacts with each other via RNA. Variants of RECC and the RESC modules, GRBC and REMC, are also emerging in studies by different labs (reviewed in [1]). These variants imply a dynamic nature of holo-editosomes that may be important in editing control and needs further characterization.…”

“…Kinetoplastid protozoa including Trypanosoma brucei are early-branching eukaryotes that require extensive insertion and deletion of uridylates in most mitochondrial mRNAs (reviewed in [1]). This RNA editing is protein-catalyzed and directed by small guide RNAs (gRNAs) with complementarity to fully-edited mRNA.…”