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Uridine insertion/deletion editing in trypanosomes: a playground for RNA‐guided information transfer

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Ruslan Aphasizhev, Inna Aphasizheva

Published Online: Mar 23 2011

DOI: 10.1002/wrna.82

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Abstract RNA editing is a collective term referring to enzymatic processes that change RNA sequence apart from splicing, 5′ capping or 3′ extension. In this article, we focus on uridine insertion/deletion mRNA editing found exclusively in mitochondria of kinetoplastid protists. This type of editing corrects frameshifts, introduces start and stops codons, and often adds much of the coding sequence to create an open reading frame. The mitochondrial genome of trypanosomatids, the most extensively studied clade within the order Kinetoplastida, is composed of ∼50 maxicircles with limited coding capacity and thousands of minicircles. To produce functional mRNAs, a multitude of nuclear‐encoded factors mediate interactions of maxicircle‐encoded pre‐mRNAs with a vast repertoire of minicircle‐encoded guide RNAs. Editing reactions of mRNA cleavage, U‐insertions or U‐deletions, and ligation are catalyzed by the RNA editing core complex (RECC, the 20S editosome) while each step of this enzymatic cascade is directed by guide RNAs. These 50–60 nucleotide (nt) molecules are 3′ uridylated by RET1 TUTase and stabilized via association with the gRNA binding complex (GRBC). Remarkably, the information transfer between maxicircle and minicircle transcriptomes does not rely on template‐dependent polymerization of nucleic acids. Instead, intrinsic substrate specificities of key enzymes are largely responsible for the fidelity of editing. Conversely, the efficiency of editing is enhanced by assembling enzymes and RNA binding proteins into stable multiprotein complexes. WIREs RNA 2011 2 669–685 DOI: 10.1002/wrna.82 This article is categorized under: RNA Processing > RNA Editing and Modification RNA Processing > Processing of Small RNAs

Modular organization of the RNA editing core complex (RECC). Direct protein–protein interactions within core complex are depicted by overlapping squares or black bars. SC, subcomplex; FR: mRNA cleavage fragment. Trans‐guided insertion and deletion, and cis‐guided insertion pathways are diagramed on the same background as corresponding endonuclease modules.

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Major RNA editing complexes and factors. GRBC‐ and RET1‐centered assemblies are likely to be more complex and participate in biogenesis of editing substrates.

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Domain organization and UTP selectivity of mitochondrial TUTases. (a) Ribbon representation illustrating the UTP bound in the deep cleft formed by the NTD and the CTD (left panel). Structural superpositions of TbMEAT1 with TbRET2 (gray) depict the overall differences in these structures, which become increasingly evident away from the active site (right panel). (b) Mechanisms of UTP specificity. Hydrogen bonds involved in uracil‐base‐specific interactions are depicted as green arrows. Invariant aspartic acid residues are indicated by asterisks.

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Low‐resolution structures of the editing core complex. (a) Reconstitution of the RECC from L. tarentolae. Shaded surface representation of three individual anti‐REL1 IgG‐decorated L‐complex particles segmented out from the 3D tomogram (in yellow). The putative IgG densities are indicated by circling. Approximate location of REL1 on unbiased single‐particle reconstruction (in blue) is shown by arrow. (Reprinted with permission from Ref 77). (b) Consensus model of the T. brucei ∼20S complex displaying a bipartite shape. Landmarks are labeled. (Reprinted with permission from Ref 83)

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Components of the RNA editing core complex from T. brucei. (Reprinted with permission from Ref 35 American Society for Biochemistry and Molecular Biology) Pum: Pumilio motif; PAPcat: catalytic domain shared among members of DNA polymerase β superfamily57; MD: middle domain; PAP CTD: C‐terminal base recognition domain.46 White Z on dark background: C2H2‐type zinc finger; OB‐fold: oligonucleotide binding fold. Black Z on light background: U1‐like C2H2 zinc finger; RNase III: RNase III catalytic‐like domain; dsRBM: double‐stranded RNA binding motif; RNase III‐Pum: overlapping RNase III‐like and Pumilio motifs; Endo–Exo–Phos: endonuclease–exonuclease–phosphatase family motif. Ligase: polynucleotide ligase‐mRNA capping catalytic domain.

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