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Mitochondrial RNA quality control in trypanosomes

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Abstract Unicellular parasites Trypanosoma brucei spp. cause African human and animal trypanosomiasis, a spectrum of diseases that jeopardize public health and afflict the economy in sub‐Saharan Africa. These hemoflagellates are distinguished by a single mitochondrion, which contains a kinetoplast nucleoid composed of DNA and histone‐like proteins. Kinetoplast DNA (kDNA) represents a densely packed network of interlinked relaxed circular molecules: a few ~23‐kb maxicircles encoding ribosomal RNAs (rRNAs) and proteins, and approximately 5,000 1‐kb minicircles bearing guide RNA (gRNA) genes. The transcription start site defines the mRNA's 5′ terminus while the primary RNA is remodeled into a monocistronic messenger by 3′–5′ exonucleolytic trimming, 5′ and 3′ end modifications, and, in most cases, by internal U‐insertion/deletion editing. Ribosomal and guide RNA precursors are also trimmed, and the processed molecules are uridylated. For 35 years, mRNA editing has attracted a major effort, but more recently the essential pre‐ and postediting processing and turnover events have been discovered and the key effectors have been identified. Among these, pentatricopeptide repeat (PPR) RNA binding proteins emerged as conduits coupling modifications of mRNA termini with internal sequence changes introduced by editing. Among 39 annotated PPRs, 20 belong to ribosomal subunits or assembly intermediates, four function as polyadenylation factors, a single factor directs 5′ mRNA modification, and one protein is found in F1‐ATPase. Nuclear and mitochondrial RNases P consist of a single PPR polypeptide, PRORP1 and PROP2, respectively. Here, we review PPR‐mediated mitochondrial processes and discuss their potential roles in mRNA maturation, quality control, translational activation, and decay. This article is categorized under: RNA Processing > Capping and 5′ End Modifications RNA Processing > 3′ End Processing RNA Processing > RNA Editing and Modification
Predicted pentatricopeptide repeat proteins of Trypanosoma brucei. PPR repeats identified by TPRpred at https://toolkit.tuebingen.mpg.de/tools/tprpred are indicated by red boxes. KPAC, kinetoplast polyadenylation complex; PPsome 5′ pyrophosphohydrolase complex
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PPR factors in mRNA biogenesis. This diagram does not imply an experimentally established temporal sequence of depicted events. For example, KPAF3 may bind G‐rich sites in mRNA precursor prior to MPsome‐catalyzed trimming. Likewise, editing may commence before trimming or adenylation. This testable model does not contradict the current state of knowledge and is meant to be challenged. The 5′ modification essential for mRNA stability is carried out by the PPsome composed of MERS1 NUDIX hydrolase and MERS2 PPR factor. MERS2 recognizes G‐rich sequences near the terminus and likely stimulates MERS1's pyrophosphohydrolytic activity. Antisense transcription initiating near mRNA 3′ end produces a double‐stranded region thereby impeding pre‐mRNA degradation by the MPsome. Although KPAF3 binding protects mRNA against MPsome attack, this factor does not play a major role in 3′ end demarcation. Instead, KPAF3 recruits KPAP1 poly(A) polymerase to the proximal 3′ terminus and enables mRNA adenylation. The A‐tailing reaction likely competes with U‐tailing by the MPsome‐embedded KRET1 TUTase. RNAs devoid of KPAF3 binding sites, such as gRNAs, undergo U‐tailing by default. KPAF4/5 poly(A) binding complex sequesters the nascent A‐tail potentially leading to mRNA uridylation blockade, hence conferring resistance to MPsome attack. KPAF4/5 interaction with the 5′ end‐bound PPsome plausibly causes mRNA circularization and provides additional stabilizing effect. KPAF3 displacement by initiating editing events consigns KPAF4/5‐bound short A‐tail for mRNA protection during editing process. Nonadenylated partially‐edited RNA lacking bound KPAF3 cannot recruit KPAF4/5 and circularize, and are rapidly degraded. Final editing events may eject the PPsome from the 5′ region causing mRNA linearization and enabling KPAF1/2 access to the 3′ end, perhaps at the cost of KPAF4/5 displacement from the short A‐tail. This RNP remodeling stimulates postediting A/U‐tailing of fully edited transcripts leading to their translational activation. It seems likely that A/U‐tailed RNA no longer requires KPAF4/5 for stability and is protected from degradation by translating ribosomes or other factors, such as KPAF1/2
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Predicted tetratricopeptide repeat proteins of Trypanosoma brucei. TPR repeats identified by TPRpred at https://toolkit.tuebingen.mpg.de/tools/tprpred are indicated by blue arrows. LSU, large ribosomal subunit
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RNA Processing > RNA Editing and Modification
RNA Processing > 3′ End Processing
RNA Processing > Capping and 5′ End Modifications

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