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High throughput sequencing revolution reveals conserved fundamentals of U‐indel editing

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Among Euglenozoans, mitochondrial RNA editing occurs in the diplonemids and in the kinetoplastids that include parasitic trypanosomes. Yet U‐indel editing, in which open reading frames (ORFs) on mRNAs are generated by insertion and deletion of uridylates in locations dictated by guide RNAs, appears confined to kinetoplastids. The nature of guide RNA and edited mRNA populations has been cursorily explored in a surprisingly extensive number of species over the years, although complete sets of fully edited mRNAs for most kinetoplast genomes are largely missing. Now, however, high throughput sequencing technologies have had an enormous impact on what we know and will learn about the mechanisms, benefits, and final edited products of U‐indel editing. Tools including PARERS, TREAT, and T‐Aligner function to organize and make sense of U‐indel mRNA transcriptomes, which are comprised of mRNAs harboring uridylate indels both consistent and inconsistent with translatable products. From high throughput sequencing data come arguments that partially edited mRNAs containing “junction regions” of noncanonical editing are editing intermediates, and conversely, arguments that they are dead‐end products. These data have also revealed that the percent of a given transcript population that is fully or partially edited varies dramatically between transcripts and organisms. Outstanding questions that are being addressed include the prevalence of sequences that apparently encode alternative ORFs, diversity of editing events in ORF termini and 5′ and 3′ untranslated regions, and the differences that exist in this byzantine process between species. High throughput sequencing technologies will also undoubtedly be harnessed to probe U‐indel editing's evolutionary origins. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Evolution and Genomics > Computational Analyses of RNA
Features of U‐indel editing. (a) U‐indel editing is a process of insertion and deletion events guided by gRNAs that contain both regions that anneal to their cognate mRNAs, and regions that will direct editing of adjacent sequence. (Reprinted with permission from Read et al. (). Copyright 2016 Wiley Periodicals, Inc.) (b) Schematic diagram depicting the associations of the RNA editing mediator complex (REMC) with the guide RNA binding complex (GRBC), and other proteins to form the RNA editing substrate binding complex (RESC). Once these protein players have assembled with mRNA and the necessary gRNA, interaction with the catalytic components of editing, the RNA edited core complexes (RECCs), can proceed. GAP1/2 are gRNA binding proteins within GRBC, and the brown dotted‐outline circles represent RESC proteins MRB7260 and MRB10130 that are not strictly REMC or GRBC components (McAdams, Simpson, Chen, Sun, & Read, ; Read et al., ). (c) Depiction of different types of mRNA molecules with origins in a single pan‐edited cryptogene. Extreme 5′ and 3′ regions of the transcript never get edited. The 3′ never edited region is the binding site of the first gRNA of the pan‐editing process. Pre‐edited sequence exists in regions yet to be edited in order to generate an mRNA encoding a canonical protein product. The bracketed forms of the mRNA represent states that are consistent with editing in progress. In these examples, the green color exists at the boundary of the editing process (junction sequence) and the molecule may represent an editing intermediate that will continue to undergo editing to eventually achieve the fully edited state shown at the bottom. The unbracketed molecules are examples of regions of alternative editing that are not in a junction position. The alternatively edited region within the canonically edited region would result in product in which the edited region contains noncanonical codons and/or a frameshift, or else a misedited product. The region of noncanonical editing upstream of the main progression of editing represents a product that is likely misedited
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Successive editing modifications successively convert junction sequence to canonically edited sequence. (a) The pre‐ and fully edited versions of a short model sequence, found within an mRNA requiring editing, are shown. (b) Example junction sequences found in this region such as those observed through high throughput sequencing. The dark blue and light blue, and violet > symbols represents editing intermediates shown in c. (c) Noted junction sequences from b have been ordered such that a progression from one junction to another can be generated by a single editing modification (underlined) from the sequence before it, beginning with the pre‐edited and ending with the fully edited sequence. On the far left is a pathway where successive noncanonical modifications progressively build up, resulting in a junction that possibly can no longer be productively re‐modified (delineated with bold u insertions). On the right, two paths of editing are shown, one with junctions resolving to the fully edited sequence (left) and the other showing a direct progression of editing (right). These pathways are based on observations in Simpson et al. ()
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Reasons for and potential fates of mRNA molecules that exhibit alternative (non‐canonical) editing patterns. Arrows represent progression of editing in a single molecule that has been color‐coded to indicate its editing state. In the first panel, the alternative sequences are present only in dead‐end edited products destined for degradation. In the second panel, the alternative sequences are part of a product with a region that is alternatively edited to generate an alternative open reading frame (ORF). In the third panel, the region with alternative editing is present in junctions that will continue to be edited until the canonical sequence is obtained
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Current state of investigation of U‐indel edited sequences from maxicircle cryptogenes among the kinetoplastids. Included studies are those in which RNA and/or DNA sequence is provided in text, figures, or supplementary material, that describe or compare pre‐, partially, or fully edited sequences of maxicircle cryptogenes. Unless indicated with the half‐moon symbol, RNA has been sequenced directly, cDNA has been cloned and sequenced, or amplified PCR products from cDNA templates have been cloned and sequenced. The structure of the tree is approximately based on models presented in Lukeš et al. (). Numbers denote the reference(s) for the analysis/es: 1. Merzlyak, Zakharova, and Kolesnikov (); 2. Benne et al. (), Feagin, Shaw, Simpson, and Stuart (), Maslov, Avila, Lake, and Simpson (), Shaw, Feagin, Stuart, and Simpson (), van der Spek et al. (), Yasuhira and Simpson (); 3. Gerasimov et al. (); 4. Bessolitsyna, Fediakov, Merzliak, and Kolesnikov (), Kolesnikov, Merzliak, Bessolitsyna, Fediakov, and Shoenian (), Merzlyak et al. (); 5. Kolesnikov et al. (); 6. Blom et al. (); 7. Bhat, Myler, and Stuart (), Shaw et al. (), Maslov et al. (), Shaw, Campbell, and Simpson (), Shaw et al. (), Souza, Myler, and Stuart (), Thiemann, Maslov, and Simpson (); 8. Maslov (); 9. Kolesnikov et al. (), Nebohácová, Kim, Simpson, and Maslov (); 10. Ramírez, Puerta, and Requena (); 11. Kolesnikov et al. (); 12. Merzlyak et al. (); 13. Landweber, Fiks, and Gilbert (), Landweber and Gilbert (), Maslov et al. (); 14. Landweber and Gilbert (), Maslov et al. (); 15. Kolesnikov et al. (), Landweber and Gilbert (), Merzlyak et al. (); 16. Landweber and Gilbert (); 17. Maslov, Hollar, Haghighat, and Nawathean (), Maslov, Nawathean, and Scheel (), Nawathean and Maslov (); 18. Gerasimov, Kostygov, Yan, and Kolesnikov (), Kolesnikov et al. (); 19. Gerasimov et al. (); 20. Gerasimov et al. (); 21. Aravin, Yurchenko, Merzlyak, and Kolesnikov (), Kolesnikov et al. (); 22. Maslov et al. (); 23. Kim, Teixeira, Kirchhoff, and Donelson (), Ochs, Otsu, Teixeira, Moser, and Kirchhoff (); 24. Ruvalcaba‐Trejo and Sturm (), Shaw, Kalem, and Zimmer (), Thomas, Martinez, Westenberger, and Sturm (), Westenberger et al. (); 25. Ruvalcaba‐Trejo and Sturm (), Westenberger et al. (); 26. Avila et al. (), Gerasimov et al. (), Maslov et al. (), Ruvalcaba‐Trejo and Sturm (), Westenberger et al. (); 27. Blom et al. (); 28. Read, Fish, Muthiani, and Stuart (), Read, Jacob, Fish, Muthiani, and Stuart (); 29. Abraham, Feagin, and Stuart (), Benne et al. (), Bhat, Koslowsky, Feagin, Smiley, and Stuart (), Carnes et al. (), Corell, Myler, and Stuart (), Decker and Sollner‐Webb (), Feagin, Abraham, and Stuart (), Feagin, Jasmer, and Stuart (), Feagin, Shaw, et al. (), Feagin and Stuart (), Kirby and Koslowsky (), Koslowsky, Bhat, Perrollaz, Feagin, and Stuart (), Read, Myler, and Stuart (), Read, Wilson, Myler, and Stuart (), Shaw et al. (), Simpson et al. (), Simpson et al. (), Souza et al. (), Souza, Shu, Read, Myler, and Stuart (); 30. Greif, Rodriguez, Reyna‐Bello, Robello, and Alvarez‐Valin (); 31. David et al. (); 32. Maslov and Simpson (), Lukeš et al. (); 33. Blom et al. (). The identities of the cultures described as Crithidia sp. KVI, Herpetomonas sp. TCC263 (Kolesnikov et al., ), and W. inconstans (Merzlyak et al., ) were not known and thus were not placed on the tree
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RNA Processing > RNA Editing and Modification

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