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mRNA Metabolism in Health and Disease
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mRNA Metabolism in Health and Disease

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 65527

Special Issue Editor

Dr. Luísa Romão

E-Mail Website
Guest Editor
Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal
Interests: nonsense-mediated mRNA decay; mRNA translational control
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The eukaryotic gene expression pathway involves a number of interlinked steps, in which messenger RNAs (mRNAs) that code for proteins and noncoding RNAs are the key intermediates. In the nucleus, the mRNA precursor is transcribed from DNA and processed, and the mature mRNA is then exported to the cytoplasm, where it is translated into protein and finally degraded. In this process, mRNAs are associated with RNA-binding proteins forming messenger ribonucleoprotein (mRNP) complexes, whose protein content evolves throughout the lifetime of the mRNA. This mRNP assembly is important for all steps of the mRNA metabolism, and is of crucial importance for correct gene expression, which is necessary to maintain cellular homeostasis. In addition, during the complex life of mRNA, cells tightly control the quality and quantity of mRNAs using various surveillance pathways. Among these is nonsense-mediated mRNA decay, which detects and degrades mRNAs carrying premature translation-termination codons introduced through DNA mutations or pre-mRNA processing defects. Besides, exciting recent data have shown that cellular RNAs can be modified post-transcriptionally with dynamic and reversible chemical modifications. These modifications can alter the structure of mRNA, modulate different steps of mRNA metabolism, and control gene expression.

This Special Issue on "mRNA Metabolism in Health and Disease" aims to provide up-to-date insight into the remarkable complexity of the mRNA metabolism, as well as on its dysregulation in the context of many different human diseases, spanning from neurological, metabolic, and cardiovascular diseases to cancer.

Dr. Luísa Romão
Guest Editor

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Keywords

  • mRNA metabolism
  • transcription
  • RNA processing
  • mRNA export and localization
  • mRNA translation
  • mRNA surveillance
  • mRNA decay
  • mRNA modifications
  • gene expression regulation
  • human genetic disease
  • cancer

Published Papers (18 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 229 KiB  
Editorial
mRNA Metabolism in Health and Disease
by Luísa Romão
Biomedicines 2022, 10(9), 2262; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10092262 - 13 Sep 2022
Viewed by 958
Abstract
Eukaryotic gene expression involves several interlinked steps, in which messenger RNAs (mRNAs), which code for proteins, are the key intermediates [...] Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)

Research

Jump to: Editorial, Review, Other

14 pages, 2183 KiB  
Article
Role of RNA Biogenesis Factors in the Processing and Transport of Human Telomerase RNA
by Tatiana Pakhomova, Maria Moshareva, Daria Vasilkova, Timofey Zatsepin, Olga Dontsova and Maria Rubtsova
Biomedicines 2022, 10(6), 1275; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061275 - 30 May 2022
Cited by 5 | Viewed by 2177
Abstract
Telomerase RNA has long been considered to be a noncoding component of telomerase. However, the expression of the telomerase RNA gene is not always associated with telomerase activity. The existence of distinct TERC gene expression products possessing different functions were demonstrated recently. During [...] Read more.
Telomerase RNA has long been considered to be a noncoding component of telomerase. However, the expression of the telomerase RNA gene is not always associated with telomerase activity. The existence of distinct TERC gene expression products possessing different functions were demonstrated recently. During biogenesis, hTR is processed by distinct pathways and localized in different cell compartments, depending on whether it functions as a telomerase complex component or facilitates antistress activities as a noncoding RNA, in which case it is either processed in the mitochondria or translated. In order to identify the factors responsible for the appearance and localization of the exact isoform of hTR, we investigated the roles of the factors regulating transcription DSIF (Spt5) and NELF-E; exosome-attracting factors ZCCHC7, ZCCHC8, and ZFC3H1; ARS2, which attracts processing and transport factors; and transport factor PHAX during the biogenesis of hTR. The data obtained revealed that ZFC3H1 participates in hTR biogenesis via pathways related to the polyadenylated RNA degradation mechanism. The data revealed essential differences that are important for understanding hTR biogenesis and that are interesting for further investigations of new, therapeutically significant targets. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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12 pages, 16480 KiB  
Article
UPF1 Inhibits Hepatocellular Carcinoma Growth through DUSP1/p53 Signal Pathway
by Suman Lee, Yukyung Hwang, Tae Hun Kim, Jaemin Jeong, Dongho Choi and Jungwook Hwang
Biomedicines 2022, 10(4), 793; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040793 - 29 Mar 2022
Cited by 5 | Viewed by 2085
Abstract
Human hepatocellular carcinoma (HCC) has a high mortality rate because of the dearth of effective treatments. Multiple studies have shown that overexpression of UPF1, a key nonsense-mediated mRNA decay (NMD) factor, reduces HCC growth through various cell signaling pathways. However, the mechanism by [...] Read more.
Human hepatocellular carcinoma (HCC) has a high mortality rate because of the dearth of effective treatments. Multiple studies have shown that overexpression of UPF1, a key nonsense-mediated mRNA decay (NMD) factor, reduces HCC growth through various cell signaling pathways. However, the mechanism by which UPF1 expression retards HCC proliferation through the regulation of RNA stability remains unclear. By employing various UPF1 variants and transcriptome analysis, we revealed that overexpression of UPF1 variants, not UPF1-mediated NMD, reduces HCC tumorigenesis. Additionally, UPF1 variant overexpression reduced tumorigenesis in xenografted mice. Transcriptome analysis indicated that the level of dual specificity phosphatase 1 (DUSP1) was increased by UPF1 variants via posttranscriptional regulation. The UPF1 overexpression-mediated increase of DUSP1 activated tumor suppressor signaling, ultimately inhibiting cell growth. In this study, we highlighted the function of UPF1 as a tumor suppressor in HCC growth. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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22 pages, 3570 KiB  
Article
Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder
by Ana Rita Marques, João Xavier Santos, Hugo Martiniano, Joana Vilela, Célia Rasga, Luísa Romão and Astrid Moura Vicente
Biomedicines 2022, 10(3), 665; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10030665 - 13 Mar 2022
Cited by 5 | Viewed by 2834
Abstract
Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with unclear etiology. Many genes have been associated with ASD risk, but the underlying mechanisms are still poorly understood. An important post-transcriptional regulatory mechanism that plays an essential role during neurodevelopment, the Nonsense-Mediated mRNA [...] Read more.
Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with unclear etiology. Many genes have been associated with ASD risk, but the underlying mechanisms are still poorly understood. An important post-transcriptional regulatory mechanism that plays an essential role during neurodevelopment, the Nonsense-Mediated mRNA Decay (NMD) pathway, may contribute to ASD risk. In this study, we gathered a list of 46 NMD factors and regulators and investigated the role of genetic variants in these genes in ASD. By conducting a comprehensive search for Single Nucleotide Variants (SNVs) in NMD genes using Whole Exome Sequencing data from 1828 ASD patients, we identified 270 SNVs predicted to be damaging in 28.7% of the population. We also analyzed Copy Number Variants (CNVs) from two cohorts of ASD patients (N = 3570) and discovered 38 CNVs in 1% of cases. Importantly, we discovered 136 genetic variants (125 SNVs and 11 CNVs) in 258 ASD patients that were located within protein domains required for NMD. These gene variants are classified as damaging using in silico prediction tools, and therefore may interfere with proper NMD function in ASD. The discovery of NMD genes as candidates for ASD in large patient genomic datasets provides evidence supporting the involvement of the NMD pathway in ASD pathophysiology. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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17 pages, 1558 KiB  
Article
New Tricks with Old Dogs: Computational Identification and Experimental Validation of New miRNA–mRNA Regulation in hiPSC-CMs
by Maja Bencun, Thiago Britto-Borges, Jessica Eschenbach and Christoph Dieterich
Biomedicines 2022, 10(2), 391; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020391 - 06 Feb 2022
Cited by 3 | Viewed by 1816
Abstract
Cardiovascular disease is still the leading cause of morbidity and mortality worldwide. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a valuable widespread in vitro model to study cardiac disease. Herein, we employ the hiPSC-CM model to identify novel miRNA–mRNA interaction partners [...] Read more.
Cardiovascular disease is still the leading cause of morbidity and mortality worldwide. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a valuable widespread in vitro model to study cardiac disease. Herein, we employ the hiPSC-CM model to identify novel miRNA–mRNA interaction partners during cardiac differentiation and β-adrenergic stress. Whole transcriptome and small RNA sequencing data were combined to identify novel miRNA–mRNA interactions. Briefly, mRNA and miRNA expression profiles were integrated with miRNA target predictions to identify significant statistical dependencies between a miRNA and its candidate target set. We show by experimental validation that our approach discriminates true from false miRNA target predictions. Thereby, we identified several differentially expressed miRNAs and focused on the two top candidates: miR-99a-5p in the context of cardiac differentiation and miR-212-3p in the context of β-adrenergic stress. We validated some target mRNA candidates by 3′UTR luciferase assays as well as in transfection experiments in the hiPSC-CM model system. Our data show that iPSC-derived cardiomyocytes and computational modeling can be used to uncover new valid miRNA–mRNA interactions beyond current knowledge. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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17 pages, 2194 KiB  
Article
Expression Profiling in Ovarian Cancer Reveals Coordinated Regulation of BRCA1/2 and Homologous Recombination Genes
by Noélia Custódio, Rosina Savisaar, Célia Carvalho, Pedro Bak-Gordon, Maria I. Ribeiro, Joana Tavares, Paula B. Nunes, Ana Peixoto, Carla Pinto, Carla Escudeiro, Manuel R. Teixeira and Maria Carmo-Fonseca
Biomedicines 2022, 10(2), 199; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020199 - 18 Jan 2022
Cited by 3 | Viewed by 2556
Abstract
Predictive biomarkers are crucial in clarifying the best strategy to use poly(ADP-ribose) polymerase inhibitors (PARPi) for the greatest benefit to ovarian cancer patients. PARPi are specifically lethal to cancer cells that cannot repair DNA damage by homologous recombination (HR), and HR deficiency is [...] Read more.
Predictive biomarkers are crucial in clarifying the best strategy to use poly(ADP-ribose) polymerase inhibitors (PARPi) for the greatest benefit to ovarian cancer patients. PARPi are specifically lethal to cancer cells that cannot repair DNA damage by homologous recombination (HR), and HR deficiency is frequently associated with BRCA1/2 mutations. Genetic tests for BRCA1/2 mutations are currently used in the clinic, but results can be inconclusive due to the high prevalence of rare DNA sequence variants of unknown significance. Most tests also fail to detect epigenetic modifications and mutations located deep within introns that may alter the mRNA. The aim of this study was to investigate whether quantitation of BRCA1/2 mRNAs in ovarian cancer can provide information beyond the DNA tests. Using the nCounter assay from NanoString Technologies, we analyzed RNA isolated from 38 ovarian cancer specimens and 11 normal fallopian tube samples. We found that BRCA1/2 expression was highly variable among tumors. We further observed that tumors with lower levels of BRCA1/2 mRNA showed downregulated expression of 12 additional HR genes. Analysis of 299 ovarian cancer samples from The Cancer Genome Atlas (TCGA) confirmed the coordinated expression of BRCA1/2 and HR genes. To facilitate the routine analysis of BRCA1/2 mRNA in the clinical setting, we developed a targeted droplet digital PCR approach that can be used with FFPE samples. In conclusion, this study underscores the potential clinical benefit of measuring mRNA levels in tumors when BRCA1/2 DNA tests are negative or inconclusive. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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12 pages, 2023 KiB  
Article
Effect of Gliadin Stimulation on HLA-DQ2.5 Gene Expression in Macrophages from Adult Celiac Disease Patients
by Federica Farina, Laura Pisapia, Mariavittoria Laezza, Gloria Serena, Antonio Rispo, Simona Ricciolino, Carmen Gianfrani, Alessio Fasano and Giovanna Del Pozzo
Biomedicines 2022, 10(1), 63; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010063 - 29 Dec 2021
Cited by 6 | Viewed by 1486
Abstract
Macrophages play an important role in the pathogenesis of celiac disease (CD) because they are involved in both inflammatory reaction and antigen presentation. We analyzed the expression of CD-associated HLA-DQ2.5 risk alleles on macrophages isolated by two cohorts of adult patients, from the [...] Read more.
Macrophages play an important role in the pathogenesis of celiac disease (CD) because they are involved in both inflammatory reaction and antigen presentation. We analyzed the expression of CD-associated HLA-DQ2.5 risk alleles on macrophages isolated by two cohorts of adult patients, from the U.S. and Italy, at different stages of disease and with different genotypes. After isolating and differentiating macrophages from PBMC, we assessed the HLA genotype and quantified the HLA-DQ2.5 mRNAs by qPCR, before and after gliadin stimulation. The results confirmed the differences in expression between DQA1*05:01 and DQB1*02:01 predisposing alleles and the non-CD associated alleles, as previously shown on other types of APCs. The gliadin challenge confirmed the differentiation of macrophages toward a proinflammatory phenotype, but above all, it triggered an increase of DQA1*05:01 mRNA, as well as a decrease of the DQB1*02:01 transcript. Furthermore, we observed a decrease in the DRB1 genes expression and a downregulation of the CIITA transactivator. In conclusion, our findings provide new evidences on the non-coordinated regulation of celiac disease DQ2.5 risk genes and support the hypothesis that gliadin could interfere in the three-dimensional arrangement of chromatin at the HLA locus. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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25 pages, 3997 KiB  
Article
A Conserved uORF Regulates APOBEC3G Translation and Is Targeted by HIV-1 Vif Protein to Repress the Antiviral Factor
by Camille Libre, Tanja Seissler, Santiago Guerrero, Julien Batisse, Cédric Verriez, Benjamin Stupfler, Orian Gilmer, Romina Cabrera-Rodriguez, Melanie M. Weber, Agustin Valenzuela-Fernandez, Andrea Cimarelli, Lucie Etienne, Roland Marquet and Jean-Christophe Paillart
Biomedicines 2022, 10(1), 13; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010013 - 22 Dec 2021
Cited by 6 | Viewed by 3224
Abstract
The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular restriction factors APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutation during reverse transcription. Vif counteracts A3G at several levels (transcription, translation, and [...] Read more.
The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular restriction factors APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutation during reverse transcription. Vif counteracts A3G at several levels (transcription, translation, and protein degradation) that altogether reduce the levels of A3G in cells and prevent its incorporation into viral particles. How Vif affects A3G translation remains unclear. Here, we uncovered the importance of a short conserved uORF (upstream ORF) located within two critical stem-loop structures of the 5′ untranslated region (5′-UTR) of A3G mRNA for this process. A3G translation occurs through a combination of leaky scanning and translation re-initiation and the presence of an intact uORF decreases the extent of global A3G translation under normal conditions. Interestingly, the uORF is also absolutely required for Vif-mediated translation inhibition and redirection of A3G mRNA into stress granules. Overall, we discovered that A3G translation is regulated by a small uORF conserved in the human population and that Vif uses this specific feature to repress its translation. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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22 pages, 7074 KiB  
Article
mRNA Analysis of Frameshift Mutations with Stop Codon in the Last Exon: The Case of Hemoglobins Campania [α1 cod95 (−C)] and Sciacca [α1 cod109 (−C)]
by Giovanna Cardiero, Gennaro Musollino, Romeo Prezioso and Giuseppina Lacerra
Biomedicines 2021, 9(10), 1390; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101390 - 04 Oct 2021
Cited by 5 | Viewed by 2491
Abstract
An insertion or deletion of a nucleotide (nt) in the penultimate or the last exon can result in a frameshift and premature termination codon (PTC), giving rise to an unstable protein variant, showing a dominant phenotype. We described two α-globin mutants created by [...] Read more.
An insertion or deletion of a nucleotide (nt) in the penultimate or the last exon can result in a frameshift and premature termination codon (PTC), giving rise to an unstable protein variant, showing a dominant phenotype. We described two α-globin mutants created by the deletion of a nucleotide in the penultimate or the last exon of the α1-globin gene: the Hb Campania or α1 cod95 (−C), causing a frameshift resulting in a PTC at codon 102, and the Hb Sciacca or α1 cod109 (−C), causing a frameshift and formation of a PTC at codon 133. The carriers showed α-thalassemia alterations (mild microcytosis with normal Hb A2) and lacked hemoglobin variants. The 3D model indicated the α-chain variants’ instability, due to the severe structural alterations with impairment of the chaperone alpha-hemoglobin stabilizing protein (AHSP) interaction. The qualitative and semiquantitative analyses of the α1mRNA from the reticulocytes of carriers highlighted a reduction in the variant cDNAs that constituted 34% (Hb Campania) and 15% (Hb Sciacca) of the total α1-globin cDNA, respectively. We developed a workflow for the in silico analysis of mechanisms triggering no-go decay, and its results suggested that the reduction in the variant mRNA was likely due to no-go decay caused by the presence of a rare triplet, and, in the case of Hb Sciacca, also by the mRNA’s secondary structure variation. It would be interesting to correlate the phenotype with the quantity of other frameshift mRNA variants, but very few data concerning α- and β-globin variants are available. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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12 pages, 856 KiB  
Communication
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes
by Rafael Graça, Rafael Fernandes, Ana Catarina Alves, Juliane Menezes, Luísa Romão and Mafalda Bourbon
Biomedicines 2021, 9(9), 1219; https://doi.org/10.3390/biomedicines9091219 - 14 Sep 2021
Cited by 5 | Viewed by 1944
Abstract
Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, characterized by increased levels of total and LDL plasma cholesterol, which leads to premature atherosclerosis and coronary heart disease. FH phenotype has considerable genetic heterogeneity and phenotypic variability, depending on LDL [...] Read more.
Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, characterized by increased levels of total and LDL plasma cholesterol, which leads to premature atherosclerosis and coronary heart disease. FH phenotype has considerable genetic heterogeneity and phenotypic variability, depending on LDL receptor activity and lifestyle. To improve diagnosis and patient management, here, we characterized two single nucleotide missense substitutions at Methionine 1 of the human LDLR gene (c.1A>T/p.(Met1Leu) and c.1A>C/p.(Met1Leu)). We used a combination of Western blot, flow cytometry, and luciferase assays to determine the effects of both variants on the expression, activity, and synthesis of LDLR. Our data show that both variants can mediate translation initiation, although the expression of variant c.1A>T is very low. Both variants are in the translation initiation codon and codify for the same amino acid p.(Met1Leu), yet they lead to different levels of impairment on LDLR expression and activity, corroborating different efficiencies of the translation initiation at these non-canonical initiation codons. The functional data of these variants allowed for an improved American College of Medical Genetics (ACMG) classification for both variants, which can allow a more personalized choice of the lipid-lowering treatment and dyslipidemia management, ultimately improving patients’ prognosis. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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28 pages, 4660 KiB  
Article
Translation of ABCE1 Is Tightly Regulated by Upstream Open Reading Frames in Human Colorectal Cells
by Joana Silva, Pedro Nina and Luísa Romão
Biomedicines 2021, 9(8), 911; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080911 - 29 Jul 2021
Cited by 5 | Viewed by 1892
Abstract
ATP-binding cassette subfamily E member 1 (ABCE1) belongs to the ABC protein family of transporters; however, it does not behave as a drug transporter. Instead, ABCE1 actively participates in different stages of translation and is also associated with oncogenic functions. Ribosome profiling analysis [...] Read more.
ATP-binding cassette subfamily E member 1 (ABCE1) belongs to the ABC protein family of transporters; however, it does not behave as a drug transporter. Instead, ABCE1 actively participates in different stages of translation and is also associated with oncogenic functions. Ribosome profiling analysis in colorectal cancer cells has revealed a high ribosome occupancy in the human ABCE1 mRNA 5′-leader sequence, indicating the presence of translatable upstream open reading frames (uORFs). These cis-acting translational regulatory elements usually act as repressors of translation of the main coding sequence. In the present study, we dissect the regulatory function of the five AUG and five non-AUG uORFs identified in the human ABCE1 mRNA 5′-leader sequence. We show that the expression of the main coding sequence is tightly regulated by the ABCE1 AUG uORFs in colorectal cells. Our results are consistent with a model wherein uORF1 is efficiently translated, behaving as a barrier to downstream uORF translation. The few ribosomes that can bypass uORF1 (and/or uORF2) must probably initiate at the inhibitory uORF3 or uORF5 that efficiently repress translation of the main ORF. This inhibitory property is slightly overcome in conditions of endoplasmic reticulum stress. In addition, we observed that these potent translation-inhibitory AUG uORFs function equally in cancer and in non-tumorigenic colorectal cells, which is consistent with a lack of oncogenic function. In conclusion, we establish human ABCE1 as an additional example of uORF-mediated translational regulation and that this tight regulation contributes to control ABCE1 protein levels in different cell environments. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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19 pages, 1704 KiB  
Article
Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer
by Lara Jürgens, Felix Manske, Elvira Hubert, Tabea Kischka, Lea Flötotto, Oliver Klaas, Victoria Shabardina, Christoph Schliemann, Wojciech Makalowski and Klaus Wethmar
Biomedicines 2021, 9(6), 618; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060618 - 29 May 2021
Cited by 6 | Viewed by 3747
Abstract
Upstream open reading frame (uORF)-mediated translational control has emerged as an important regulatory mechanism in human health and disease. However, a systematic search for cancer-associated somatic uORF mutations has not been performed. Here, we analyzed the genetic variability at canonical (uAUG) and alternative [...] Read more.
Upstream open reading frame (uORF)-mediated translational control has emerged as an important regulatory mechanism in human health and disease. However, a systematic search for cancer-associated somatic uORF mutations has not been performed. Here, we analyzed the genetic variability at canonical (uAUG) and alternative translational initiation sites (aTISs), as well as the associated upstream termination codons (uStops) in 3394 whole-exome-sequencing datasets from patient samples of breast, colon, lung, prostate, and skin cancer and of acute myeloid leukemia, provided by The Cancer Genome Atlas research network. We found that 66.5% of patient samples were affected by at least one of 5277 recurrent uORF-associated somatic single nucleotide variants altering 446 uAUG, 347 uStop, and 4733 aTIS codons. While twelve uORF variants were detected in all entities, 17 variants occurred in all five types of solid cancer analyzed here. Highest frequencies of individual somatic variants in the TLSs of NBPF20 and CHCHD2 reached 10.1% among LAML and 8.1% among skin cancer patients, respectively. Functional evaluation by dual luciferase reporter assays identified 19 uORF variants causing significant translational deregulation of the associated main coding sequence, ranging from 1.73-fold induction for an AUG.1 > UUG variant in SETD4 to 0.006-fold repression for a CUG.6 > GUG variant in HLA-DRB1. These data suggest that somatic uORF mutations are highly prevalent in human malignancies and that defective translational regulation of protein expression may contribute to the onset or progression of cancer. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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12 pages, 52875 KiB  
Communication
Translational Attenuation by an Intron Retention in the 5′ UTR of ENAM Causes Amelogenesis Imperfecta
by Youn Jung Kim, Yejin Lee, Hong Zhang, John Timothy Wright, James P. Simmer, Jan C.-C. Hu and Jung-Wook Kim
Biomedicines 2021, 9(5), 456; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050456 - 22 Apr 2021
Cited by 4 | Viewed by 1896
Abstract
Amelogenesis imperfecta (AI) is a collection of rare genetic conditions affecting tooth enamel. The affected enamel can be of insufficient quantity and/or altered quality, impacting structural content, surface integrity and coloration. Heterozygous mutations in ENAM result in hypoplastic AI without other syndromic phenotypes, [...] Read more.
Amelogenesis imperfecta (AI) is a collection of rare genetic conditions affecting tooth enamel. The affected enamel can be of insufficient quantity and/or altered quality, impacting structural content, surface integrity and coloration. Heterozygous mutations in ENAM result in hypoplastic AI without other syndromic phenotypes, with variable expressivity and reduced penetrance, unlike other AI-associated genes. In this study, we recruited a Caucasian family with hypoplastic AI. Mutational analysis (using whole exome sequencing) revealed a splicing donor site mutation (NM_031889.3: c. −61 + 1G > A). Mutational effects caused by this variant were investigated with a minigene splicing assay and in vitro expression analysis. The mutation resulted in a retention of intron 1 and exon 2 (a normally skipped exon), and this elongated 5′ UTR sequence attenuated the translation from the mutant mRNA. Structure and translation predictions raised the possibility that the long complex structures—especially a hairpin structure located right before the translation initiation codon of the mutant mRNA—caused reduced protein expression. However, there could be additional contributing factors, including additional uORFs. For the first time, we determined that a mutation altered the ENAM 5′ UTR, but maintained the normal coding amino acid sequence, causing hypoplastic AI. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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Review

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22 pages, 1100 KiB  
Review
Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey
by Paulo J. da Costa, Malika Hamdane, Luc Buée and Franck Martin
Biomedicines 2022, 10(2), 241; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020241 - 23 Jan 2022
Cited by 6 | Viewed by 4544
Abstract
Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger [...] Read more.
Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger many neurodegenerative diseases termed tauopathies, of which Alzheimer’s disease (AD) is the figurehead. Such pathological aggregation processes are critical for the onset of these diseases. Among the various causes of tau protein pathogenicity, abnormal tau mRNA metabolism, expression and dysregulation of tau post-translational modifications are critical steps. Moreover, the relevance of tau function to general mRNA metabolism has been highlighted recently in tauopathies. In this review, we mainly focus on how mRNA metabolism impacts the onset and development of tauopathies. Thus, we intend to portray how mRNA metabolism of, or mediated by, tau is associated with neurodegenerative diseases. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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23 pages, 962 KiB  
Review
Dynamic Variations of 3′UTR Length Reprogram the mRNA Regulatory Landscape
by Estanislao Navarro, Adrián Mallén and Miguel Hueso
Biomedicines 2021, 9(11), 1560; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111560 - 28 Oct 2021
Cited by 23 | Viewed by 4168
Abstract
This paper concerns 3′-untranslated regions (3′UTRs) of mRNAs, which are non-coding regulatory platforms that control stability, fate and the correct spatiotemporal translation of mRNAs. Many mRNAs have polymorphic 3′UTR regions. Controlling 3′UTR length and sequence facilitates the regulation of the accessibility of functional [...] Read more.
This paper concerns 3′-untranslated regions (3′UTRs) of mRNAs, which are non-coding regulatory platforms that control stability, fate and the correct spatiotemporal translation of mRNAs. Many mRNAs have polymorphic 3′UTR regions. Controlling 3′UTR length and sequence facilitates the regulation of the accessibility of functional effectors (RNA binding proteins, miRNAs or other ncRNAs) to 3′UTR functional boxes and motifs and the establishment of different regulatory landscapes for mRNA function. In this context, shortening of 3′UTRs would loosen miRNA or protein-based mechanisms of mRNA degradation, while 3′UTR lengthening would strengthen accessibility to these effectors. Alterations in the mechanisms regulating 3′UTR length would result in widespread deregulation of gene expression that could eventually lead to diseases likely linked to the loss (or acquisition) of specific miRNA binding sites. Here, we will review the mechanisms that control 3′UTR length dynamics and their alterations in human disorders. We will discuss, from a mechanistic point of view centered on the molecular machineries involved, the generation of 3′UTR variability by the use of alternative polyadenylation and cleavage sites, of mutually exclusive terminal alternative exons (exon skipping) as well as by the process of exonization of Alu cassettes to generate new 3′UTRs with differential functional features. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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12 pages, 1376 KiB  
Review
Disease Mechanisms and Therapeutic Approaches in C9orf72 ALS-FTD
by Keith Mayl, Christopher E. Shaw and Youn-Bok Lee
Biomedicines 2021, 9(6), 601; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060601 - 25 May 2021
Cited by 7 | Viewed by 4416
Abstract
A hexanucleotide repeat expansion mutation in the first intron of C9orf72 is the most common known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Since the discovery in 2011, numerous pathogenic mechanisms, including both loss and gain of function, have been proposed. [...] Read more.
A hexanucleotide repeat expansion mutation in the first intron of C9orf72 is the most common known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Since the discovery in 2011, numerous pathogenic mechanisms, including both loss and gain of function, have been proposed. The body of work overall suggests that toxic gain of function arising from bidirectionally transcribed repeat RNA is likely to be the primary driver of disease. In this review, we outline the key pathogenic mechanisms that have been proposed to date and discuss some of the novel therapeutic approaches currently in development. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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26 pages, 5171 KiB  
Review
From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies
by Hironori Adachi, Martin Hengesbach, Yi-Tao Yu and Pedro Morais
Biomedicines 2021, 9(5), 550; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050550 - 14 May 2021
Cited by 41 | Viewed by 8150
Abstract
Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms [...] Read more.
Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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9 pages, 2147 KiB  
Case Report
Role of RNA in Molecular Diagnosis of MADD Patients
by Célia Nogueira, Lisbeth Silva, Ana Marcão, Carmen Sousa, Helena Fonseca, Hugo Rocha, Teresa Campos, Elisa Leão Teles, Esmeralda Rodrigues, Patrícia Janeiro, Ana Gaspar and Laura Vilarinho
Biomedicines 2021, 9(5), 507; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050507 - 04 May 2021
Cited by 4 | Viewed by 2187
Abstract
The electron-transfer flavoprotein dehydrogenase gene (ETFDH) encodes the ETF-ubiquinone oxidoreductase (ETF-QO) and has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). In this study, we present the clinical and molecular diagnostic challenges, at the DNA and [...] Read more.
The electron-transfer flavoprotein dehydrogenase gene (ETFDH) encodes the ETF-ubiquinone oxidoreductase (ETF-QO) and has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). In this study, we present the clinical and molecular diagnostic challenges, at the DNA and RNA levels, involved in establishing the genotype of four MADD patients with novel ETFDH variants: a missense variant, two deep intronic variants and a gross deletion. RNA sequencing allowed the identification of the second causative allele in all studied patients. Simultaneous DNA and RNA investigation can increase the number of MADD patients that can be confirmed following the suggestive data results of an expanded newborn screening program. In clinical practice, accurate identification of pathogenic mutations is fundamental, particularly with regard to diagnostic, prognostic, therapeutic and ethical issues. Our study highlights the importance of RNA studies for a definitive molecular diagnosis of MADD patients, expands the background of ETFDH mutations and will be important in providing an accurate genetic counseling and a prenatal diagnosis for the affected families. Full article
(This article belongs to the Special Issue mRNA Metabolism in Health and Disease)
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