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Deciphering molecular mechanisms of mRNA metabolism in the deep‐branching eukaryote Entamoeba histolytica

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Although extraordinary rapid advance has been made in the knowledge of mechanisms regulating messenger RNA (mRNA) metabolism in mammals and yeast, little information is known in deep‐branching eukaryotes. The complete genome sequence of Entamoeba histolytica, the protozoan parasite responsible for human amoebiasis, provided a lot of information for the identification and comparison of regulatory sequences and proteins potentially involved in mRNA synthesis, processing, and degradation. Here, we review the current knowledge of mRNA metabolism in this human pathogen. Several DNA motifs in promoter and nuclear factors involved in transcription, as well as conserved polyadenylation sequences in mRNA 3′‐untranslated region and possible cleavage and polyadenylation factors, are described. In addition, we present recent data about proteins involved in mRNA decay with a special focus on the recently reported P‐bodies in amoeba. Models for mechanisms of decapping and deadenylation‐dependent pathways are discussed. We also review RNA‐based gene silencing mechanisms and describe the DEAD/DExH box RNA helicases that are molecular players in all mRNA metabolism reactions. The functional characterization of selected proteins allows us to define a general framework to describe how mRNA synthesis, processing, and decay may occur in E. histolytica. Taken altogether, studies of mRNA metabolism in this single‐celled eukaryotic model suggest the conservation of specific gene expression regulatory events through evolution. WIREs RNA 2014, 5:247–262. doi: 10.1002/wrna.1205 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Processing > 3' End Processing RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution

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Messenger RNA (mRNA) life cycle. Transcript synthesis, to translation and degradation occur in the form of dynamic protein‐bound messenger ribonucleoprotein complexes (mRNPs). Within an mRNP complex, a transcript is bound by a changing set of proteins that mediate the cotranscriptional and post‐transcriptional events that make up an mRNA life cycle. Precursor mRNAs are synthesized in nucleus by RNA polymerase II. Then, transcripts undergo capping, splicing, and 3′‐end cleavage and polyadenylation in a cotranscriptional coupled reaction. Mature mRNAs are exported to the cytoplasm, translated to proteins in ribosomes, and then degraded. Remarkably, mRNA degradation and storage occur in cytoplasmic structures denoted as P‐body. The mRNA decay starts with the deadenylation reaction followed by mRNA body degradation in 5′ → 3′ direction (decapping and 5′ → 3′decay) or alternatively deadenylated transcripts are reduced in 3′ → 5′ direction by the exosome complex and decapping enzymes. The mRNAs are subject to surveillance mechanisms, which check for the presence of premature stop codons. Upon detection of nonsense codons, aberrant mRNAs are degraded through nonsense‐mediated decay.
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Comparison of the major messenger RNA (mRNA) degradation pathways in Entamoeba histolytica and Homo sapiens. Upper panel: Decapping (5′ → 3′ decay) proteins. H. sapiens has the decapping enzymes DCP1, DCP2, DCP‐scavenger (DCPs), and EDC1–3, DHH1, PAT1, Hedls, and Lsm1–7‐associated proteins. Of these, E. histolytica lacks DCP1, XRN1, Pat1, Hedls, and Lsm5 protein‐encoding genes. Middle panel: Deadenylation (3′ → 5′ decay). E. histolytica contains an incomplete CCR4–CAF1–NOT complex. Amoeba has genes for CAF1, CAF1‐like, NOT1–4, and PABP proteins, whereas CCR4, NOT5, PARN, and PAN2‐PAN3 deadenylases are lacking, as well as the accessory TOB and RHAU proteins. Lower panel: Exosome (3′ → 5′ decay): E. histolytica contains almost all genes described for human exosome, but it lacks the RRP45 and Csl4 protein‐encoding genes. Geometric shapes with continuous outline correspond to proteins present in both H. sapiens and E. histolytica. Geometric shapes with dotted outline indicate proteins that are absent in E. histolytica.
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Prediction of amino acid residues of EhCFIm25 that could interact with RNA. (a) Overlapping of predicted three‐dimensional model of EhCFIm25 (green) with crystallographic structure of human CFIm25 (gray). (b and c) Magnification showing the proximity of L135 (b) and Y217 (c) amino acid residues in EhCFIm25 with RNA. RNA template sequence is denoted in red.
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Comparison of polyadenylation sequences among eukaryotic organisms. Left, a simplified version of the eukaryotic evolutionary tree. Right, pre‐messenger RNA (mRNA) 3′‐untranslated region (UTR) with polyadenylation sequences reported for a representative species of each arm.
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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution
RNA Processing > 3′ End Processing
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

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