Key result
The 3010-MRB complex serves as a major scaffold for kinetoplastid RNA editing, while the REH2-MRB complex contains a critical trans-acting RNA helicase (REH2) that affects multiple steps of editing function.
This basic science study identifies specialized functions of MRB1 subcomplexes in Trypanosoma brucei, revealing that the REH2 helicase regulates RNA editing in trans within the 3010-MRB scaffold.
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Hypothesis-generating for antiparasitic RNA-editing inhibitors; leaves open in vivo efficacy and clinical translation.
Adaptation and survival of Trypanosoma brucei requires editing of mitochondrial mRNA by uridylate (U) insertion and deletion. Hundreds of small guide RNAs (gRNAs) direct the mRNA editing at over 3,000 sites. RNA editing is controlled during the life cycle but the regulation of substrate and stage specificity remains unknown. Editing progresses in the 3' to 5' direction along the pre-mRNA in blocks, each targeted by a unique gRNA. A critical editing factor is the mitochondrial RNA binding complex 1 (MRB1) that binds gRNA and transiently interacts with the catalytic RNA editing core complex (RECC). MRB1 is a large and dynamic complex that appears to be comprised of distinct but related subcomplexes (termed here MRBs). MRBs seem to share a 'core' complex of proteins but differ in the composition of the 'variable' proteins. Since some proteins associate transiently the MRBs remain imprecisely defined. MRB1 controls editing by unknown mechanisms, and the functional relevance of the different MRBs is unclear. We previously identified two distinct MRBs, and showed that they carry mRNAs that undergo editing. We proposed that editing takes place in the MRBs because MRBs stably associate with mRNA and gRNA but only transiently interact with RECC, which is RNA free. Here, we identify the first specialized functions in MRBs: 1) 3010-MRB is a major scaffold for RNA editing, and 2) REH2-MRB contains a critical trans-acting RNA helicase (REH2) that affects multiple steps of editing function in 3010-MRB. These trans effects of the REH2 include loading of unedited mRNA and editing in the first block and in subsequent blocks as editing progresses. REH2 binds its own MRB via RNA, and conserved domains in REH2 were critical for REH2 to associate with the RNA and protein components of its MRB. Importantly, REH2 associates with a ~30 kDa RNA-binding protein in a novel ~15S subcomplex in RNA-depleted mitochondria. We use these new results to update our model of MRB function and organization.
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Madina et al. (2015) studied Trypanosoma brucei RNA editing. REH2 RNAi knockdown and MRB1 complex variants vs. Wild-type or uninduced cells was evaluated on RNA editing efficiency and MRB1 complex composition. The 3010-MRB complex serves as a major scaffold for kinetoplastid RNA editing, while the REH2-MRB complex contains a critical trans-acting RNA helicase (REH2) that affects multiple steps of editing function.
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