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

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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
RNA editing core complex (RECC). (a) Basic reaction steps at each editing site include guide RNA‐directed cleavage of the mRNA, followed by either a 3′‐U exonuclease or a 3′ TUTase acting on the 3′‐end of the cleaved upstream fragment, then resealing of the mRNA by RNA ligase. The gRNA‐directed cleavage reactions at U‐deletional and U‐insertional editing sites require distinct endonucleases with different cleavage reaction mechanisms: the former requires an adenylate nucleotide (+), while the latter is inhibited by adenylates (−). (b) Editing by multiple gRNAs. The initiating gRNA (gRNA‐1) and subsequent gRNAs (gRNA‐2…gRNA‐n) are depicted with pre‐edited, partially edited, and fully edited mRNA. After a full block of editing is completed (depicted by a continuous duplex) the responsible gRNA is replaced by the next upstream gRNA. The exiting gRNA is thought to be degraded by a putative “discard” pathway (depicted by a broken line). (c) Variants of the RECC with shared proteins and alternative endonuclease modules for insertion and deletion editing. Note that B9 and B10 are not canonical RECC proteins because they are not regularly observed in the purifications of RECC. B9 and B10 may be only found in a subset of complexes and are depicted in a box to distinguish them from canonical RECC proteins. BS3 cross‐links between RNase III (RIII)‐like proteins are indicated with lines. (d) Summary of the combinatorial potential of RIII‐like proteins based on the BS3 cross‐linking data in panel c. Additional potential interactions between RIII‐like proteins including X1 and A‐proteins are included
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Accessory editing components of the RNA editing core complex (RECC) enzyme. Core and accessory components of the editing apparatus assemble around the mRNA substrates. These include the gRNA‐bound RESC subcomplex, the REH2C helicase subcomplex, a MRB1590/6070‐containing subcomplex, and REH1 helicase. The core RECC enzyme and its accessory editing factors have been found to associate with each other via transient RNA‐mediated interactions. RESC is divided into two functionally distinct modules, the gRNA‐binding complex (GRBC) and RNA editing mediator complex (REMC). Several RESC proteins may be critical for the integrity and organization of RESC. MRB8620, a canonical GRBC protein, may control the assembly of the GRBC/REMC modules in RESC (MRB8620 is depicted as a dotted box bridging the two modules). MRB7260 binds weakly with RESC proteins and is not a canonical protein. It may be an assembly factor of RESC. Purifications of RESC and REH2C proteins were shown to contain mRNA substrates and products of editing. This supports a current model of the RNA editing machinery in which RESC‐mediated targeting of mRNA or its mRNPs creates suitable mRNA–gRNA hybrid substrates for the RECC and RNA helicase enzymes and other factors during concerted phases of editing: substrate recognition, editing initiation and progression, complex organization and co‐complex dynamics. Identified variants of RECC, RESC and potentially other mRNA trans factors may provide additional layers of complexity and control points in editing
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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Processing > RNA Editing and Modification

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