Mitochondrial Dual-coding Genes in<i>Trypanosoma</i>brucei

Kirby, Laura E.; Koslowsky, Donna J.

doi:10.1101/187732

Cited by 5 publications

(11 citation statements)

References 71 publications

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“…Small alternative editing events that result in frameshifts, particularly near the 5’ end of the editing domain, would cause the formation of an alternative N‐terminus or else an ORF with an entirely different sequence. These have been identified or inferred in T. brucei (Kirby & Koslowsky, ; Koslowsky et al, ; Madej, Niemann, Hüttenhofer, & Göringer, ; Madina et al, ; Ochsenreiter, Cipriano, & Hajduk, ; Simpson et al, ). The noncanonical L. pyrrhocoris and T. cruzi full length ORF reconstructions with highest support were those in which one or a few alternative editing events in a discrete region shift the reading frame such that the encoded protein contains a canonical central domain with an altered N‐ or C‐terminus (Gerasimov et al, ).…”

Section: Knowledge Gained From High Throughput Sequencing Methodologiesmentioning

confidence: 94%

“…Evidence that noncanonical editing generates alternative ORFs, as shown in the middle panel in Figure , has been extensively sought with some success. Alternatively edited mRNA molecules or reconstructed ORFs have been identified in T. brucei , T. cruzi , L. mexicana , L. pyrrhocoris , and Perkinsela (Gerasimov et al, ; Kirby & Koslowsky, ; Madina et al, ; Maslov, ; Ochsenreiter & Hajduk, ; Read et al, ; Read, Wilson, et al, ; Simpson et al, ). The more targeted studies have also identified the gRNAs that could direct these alternative editing events (Kirby & Koslowsky, ; Madina et al, ; Ochsenreiter & Hajduk, ).…”

Section: Knowledge Gained From High Throughput Sequencing Methodologiesmentioning

confidence: 99%

“…Alternatively edited mRNA molecules or reconstructed ORFs have been identified in T. brucei , T. cruzi , L. mexicana , L. pyrrhocoris , and Perkinsela (Gerasimov et al, ; Kirby & Koslowsky, ; Madina et al, ; Maslov, ; Ochsenreiter & Hajduk, ; Read et al, ; Read, Wilson, et al, ; Simpson et al, ). The more targeted studies have also identified the gRNAs that could direct these alternative editing events (Kirby & Koslowsky, ; Madina et al, ; Ochsenreiter & Hajduk, ). In the most complete pursuit of such products, identification of an alternatively edited mRNA, a potential causative gRNA, and antibody‐detectable protein product arising from the T. brucei COIII cryptogene were identified (Ochsenreiter, Anderson, Wood, & Hajduk, ; Ochsenreiter & Hajduk, ).…”

Section: Knowledge Gained From High Throughput Sequencing Methodologiesmentioning

confidence: 99%

“…High throughput methods can now tell us how common this junction‐generating mechanism likely is. Already, high throughput maxicircle transcriptome output in T. brucei has been directly compared to gRNA coverage maps to support models of proteins that affect either progression through a gRNA or gRNA exchange (Kirby & Koslowsky, ; McAdams et al, ; Simpson et al, , ). Moreover, early studies suggesting that gRNAs are consumed during editing were confirmed by Aphasizheva et al () by using high throughput sequencing to interrogate the gRNA population in cells in which editing was inhibited.…”

Section: Knowledge Gained From High Throughput Sequencing Methodologiesmentioning

confidence: 99%

“…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.…”

Section: Early Studies Map the Basic U‐indel Edited Transcript Landscapementioning

confidence: 99%

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

2018

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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.

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Section: Knowledge Gained From High Throughput Sequencing Methodologiesmentioning

confidence: 94%

Section: Knowledge Gained From High Throughput Sequencing Methodologiesmentioning

confidence: 99%

Section: Knowledge Gained From High Throughput Sequencing Methodologiesmentioning

confidence: 99%

Section: Knowledge Gained From High Throughput Sequencing Methodologiesmentioning

confidence: 99%

Section: Early Studies Map the Basic U‐indel Edited Transcript Landscapementioning

confidence: 99%

See 3 more Smart Citations

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

2018

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

et al. 2018

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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.

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Intrinsic and regulated properties of minimally edited trypanosome mRNAs

Tylec

Simpson

Kirby

et al. 2019

Nucleic Acids Research

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Most mitochondrial mRNAs in kinetoplastids require extensive uridine insertion/deletion editing to generate translatable open reading frames. Editing is specified by trans-acting gRNAs and involves a complex machinery including basal and accessory factors. Here, we utilize high-throughput sequencing to analyze editing progression in two minimally edited mRNAs that provide a simplified system due their requiring only two gRNAs each for complete editing. We show that CYb and MURF2 mRNAs exhibit barriers to editing progression that differ from those previously identified for pan-edited mRNAs, primarily at initial gRNA usage and gRNA exchange. We demonstrate that mis-edited junctions arise through multiple pathways including mis-alignment of cognate gRNA, incorrect and sometimes promiscuous gRNA utilization and inefficient gRNA anchoring. We then examined the roles of accessory factors RBP16 and MRP1/2 in maintaining edited CYb and MURF2 populations. RBP16 is essential for initiation of CYb and MURF2 editing, as well as MURF2 editing progression. In contrast, MRP1/2 stabilizes both edited mRNA populations, while further promoting progression of MURF2 mRNA editing. We also analyzed the effects of RNA Editing Substrate Binding Complex components, TbRGG2 and GAP1, and show that both proteins modestly impact progression of editing on minimally edited mRNAs, suggesting a novel function for GAP1.

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Mitochondrial Dual-coding Genes inTrypanosomabrucei

Cited by 5 publications

References 71 publications

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

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

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

Intrinsic and regulated properties of minimally edited trypanosome mRNAs

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