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Science (New York, N.Y.) Jun 2016The eukaryotic 5' untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control... (Review)
Review
The eukaryotic 5' untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control of translation efficiency and shaping the cellular proteome. The ribosomal initiation complex is assembled on the mRNA via a cap-dependent or cap-independent mechanism. We describe various mechanisms controlling ribosome scanning and initiation codon selection by 5' upstream open reading frames, translation initiation factors, and primary and secondary structures of the 5'UTR, including particular sequence motifs. We also discuss translational control via phosphorylation of eukaryotic initiation factor 2, which is implicated in learning and memory, neurodegenerative diseases, and cancer.
Topics: 5' Untranslated Regions; Animals; Codon, Initiator; Eukaryotic Initiation Factor-2; Humans; Memory; Neoplasms; Neurodegenerative Diseases; Open Reading Frames; Peptide Chain Initiation, Translational; Regulatory Elements, Transcriptional; Ribosomes
PubMed: 27313038
DOI: 10.1126/science.aad9868 -
International Journal of Molecular... Feb 2023As it is well known, messenger RNA has many regulatory regions along its sequence length. One of them is the 5' untranslated region (5'UTR), which itself contains many... (Review)
Review
As it is well known, messenger RNA has many regulatory regions along its sequence length. One of them is the 5' untranslated region (5'UTR), which itself contains many regulatory elements such as upstream ORFs (uORFs), internal ribosome entry sites (IRESs), microRNA binding sites, and structural components involved in the regulation of mRNA stability, pre-mRNA splicing, and translation initiation. Activation of the alternative, more upstream transcription start site leads to an extension of 5'UTR. One of the consequences of 5'UTRs extension may be head-to-head gene overlap. This review describes elements in 5'UTR of protein-coding transcripts and the functional significance of protein-coding genes 5' overlap with implications for transcription, translation, and disease.
Topics: 5' Untranslated Regions; Protein Biosynthesis; RNA, Messenger; Gene Expression Regulation; Regulatory Sequences, Nucleic Acid
PubMed: 36769304
DOI: 10.3390/ijms24032976 -
Nucleic Acids Research Sep 2022Chemical modifications are important for RNA function and metabolism. N4-acetylcytidine (ac4C) is critical for the translation and stability of mRNA. Although ac4C is...
Chemical modifications are important for RNA function and metabolism. N4-acetylcytidine (ac4C) is critical for the translation and stability of mRNA. Although ac4C is found in RNA viruses, the detailed mechanisms through which ac4C affects viral replication are unclear. Here, we reported that the 5' untranslated region of the enterovirus 71 (EV71) genome was ac4C modified by the host acetyltransferase NAT10. Inhibition of NAT10 and mutation of the ac4C sites within the internal ribosomal entry site (IRES) suppressed EV71 replication. ac4C enhanced viral RNA translation via selective recruitment of PCBP2 to the IRES and boosted RNA stability. Additionally, ac4C increased the binding of RNA-dependent RNA polymerase (3D) to viral RNA. Notably, ac4C-deficient mutant EV71 showed reduced pathogenicity in vivo. Our findings highlighted the essential role of ac4C in EV71 infection and provided insights into potential antiviral treatments.
Topics: Enterovirus A, Human; RNA, Viral; Enterovirus; Virulence; Internal Ribosome Entry Sites; 5' Untranslated Regions; Virus Replication
PubMed: 35971620
DOI: 10.1093/nar/gkac675 -
Genes Feb 2022Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and... (Review)
Review
Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and gastrointestinal system. There are two genetically distinct types of myotonic dystrophy: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), both dominantly inherited with significant overlap in clinical manifestations. DM1 results from CTG repeat expansions in the 3'-untranslated region (3'UTR) of the (dystrophia myotonica protein kinase) gene on chromosome 19, while DM2 is caused by CCTG repeat expansions in intron 1 of the (cellular nucleic acid-binding protein) gene on chromosome 3. Recent advances in genetics and molecular biology, especially in the field of RNA biology, have allowed better understanding of the potential pathomechanisms involved in DM. In this review article, core clinical features and genetics of DM are presented followed by a discussion on the current postulated pathomechanisms and therapeutic approaches used in DM, including the ones currently in human clinical trial phase.
Topics: 3' Untranslated Regions; Brain; Heart; Humans; Myotonic Dystrophy
PubMed: 35205411
DOI: 10.3390/genes13020367 -
Genes & Development Oct 2010The intricacies of p53 regulation just got more complex. While much is known about the transcriptional regulation of p53 target genes, Chen and Kastan (pp. 2146-2156)...
The intricacies of p53 regulation just got more complex. While much is known about the transcriptional regulation of p53 target genes, Chen and Kastan (pp. 2146-2156) uncovered a new mechanism regarding the making of the p53 protein itself. In the October 1, 2010, issue of Genes & Development, they introduced us to a novel mechanism of p53 translational control, by which a 5'-3' cap-independent, poly(A)-independent, RNA-RNA interaction enhances p53 translation by binding the ribosomal protein RPL26 following DNA damage. Oligonucleotides designed against this 5'-3' untranslated region (UTR) duplex disrupted the binding of RPL26 to p53 mRNA and reduced p53 synthesis and, therefore, function. This study reveals an alternate mechanism of translational control to regulate p53 levels.
Topics: 3' Untranslated Regions; 5' Untranslated Regions; Humans; Oligonucleotides; Protein Binding; Protein Biosynthesis; RNA, Messenger; Ribosomal Proteins; Tumor Suppressor Protein p53
PubMed: 20952532
DOI: 10.1101/gad.1988510 -
RNA Biology Jan 2022The Androgen Receptor (AR), transcriptionally activated by its ligands, testosterone and dihydrotestosterone (DHT), is widely expressed in cells and tissues, influencing... (Review)
Review
The Androgen Receptor (AR), transcriptionally activated by its ligands, testosterone and dihydrotestosterone (DHT), is widely expressed in cells and tissues, influencing normal biology and disease states. The protein product of the AR gene is involved in the regulation of numerous biological functions, including the development and maintenance of the normal prostate gland and of the cardiovascular, musculoskeletal and immune systems. Androgen signalling, mediated by AR protein, plays a crucial role in the development of prostate cancer (PCa), and is presumed to be involved in other cancers including those of the breast, bladder, liver and kidney. Significant research and reviews have focused on AR protein function; however, inadequate research and literature exist to define the function of AR mRNA in normal and cancer cells. The AR mRNA transcript is nearly 11 Kb long and contains a long 3' untranslated region (UTR), suggesting its biological role in post-transcriptional regulation, consequently affecting the overall functions of both normal and cancer cells. Research has demonstrated that many biological activities, including RNA stability, translation, cellular trafficking and localization, are associated with the 3' UTRs of mRNAs. In this review, we describe the potential role of the AR 3' UTR and summarize RNA-binding proteins (RBPs) that interact with the AR mRNA to regulate post-transcriptional metabolism. We highlight the importance of AR mRNA as a critical modulator of carcinogenesis and its important role in developing therapy-resistant prostate cancer.
Topics: 3' Untranslated Regions; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; RNA, Messenger; Receptors, Androgen
PubMed: 35704670
DOI: 10.1080/15476286.2022.2084839 -
International Journal of Molecular... Mar 2020Translation of the hepatitis C virus (HCV) RNA genome is regulated by the internal ribosome entry site (IRES), located in the 5'-untranslated region (5'UTR) and part of... (Review)
Review
Translation of the hepatitis C virus (HCV) RNA genome is regulated by the internal ribosome entry site (IRES), located in the 5'-untranslated region (5'UTR) and part of the core protein coding sequence, and by the 3'UTR. The 5'UTR has some highly conserved structural regions, while others can assume different conformations. The IRES can bind to the ribosomal 40S subunit with high affinity without any other factors. Nevertheless, IRES activity is modulated by additional sequences in the viral genome, including the 3'UTR and the -acting replication element (CRE). Canonical translation initiation factors (eIFs) are involved in HCV translation initiation, including eIF3, eIF2, eIF1A, eIF5, and eIF5B. Alternatively, under stress conditions and limited eIF2-Met-tRNA availability, alternative initiation factors such as eIF2D, eIF2A, and eIF5B can substitute for eIF2 to allow HCV translation even when cellular mRNA translation is downregulated. In addition, several IRES trans-acting factors (ITAFs) modulate IRES activity by building large networks of RNA-protein and protein-protein interactions, also connecting 5'- and 3'-ends of the viral RNA. Moreover, some ITAFs can act as RNA chaperones that help to position the viral AUG start codon in the ribosomal 40S subunit entry channel. Finally, the liver-specific microRNA-122 (miR-122) stimulates HCV IRES-dependent translation, most likely by stabilizing a certain structure of the IRES that is required for initiation.
Topics: 3' Untranslated Regions; 5' Untranslated Regions; Codon, Initiator; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-3; Eukaryotic Initiation Factors; Genome, Viral; Hepacivirus; Hepatitis C; Humans; Internal Ribosome Entry Sites; MicroRNAs; Models, Molecular; Peptide Chain Initiation, Translational; Protein Biosynthesis; RNA, Viral; Ribosome Subunits, Small, Eukaryotic; Ribosomes
PubMed: 32230899
DOI: 10.3390/ijms21072328 -
Viruses Jun 2017Flaviviruses are enveloped arthropod-borne viruses with a single-stranded, positive-sense RNA genome that can cause serious illness in humans and animals. The 11 kb 5'... (Review)
Review
Flaviviruses are enveloped arthropod-borne viruses with a single-stranded, positive-sense RNA genome that can cause serious illness in humans and animals. The 11 kb 5' capped RNA genome consists of a single open reading frame (ORF), and is flanked by 5' and 3' untranslated regions (UTR). The ORF is a polyprotein that is processed into three structural and seven non-structural proteins. The UTRs have been shown to be important for viral replication and immune modulation. Both of these regions consist of elements that are essential for genome cyclization, resulting in initiation of RNA synthesis. Genome mutation studies have been employed to investigate each component of the essential elements to show the necessity of each component and its role in viral RNA replication and growth. Furthermore, the highly structured 3'UTR is responsible for the generation of subgenomic flavivirus RNA (sfRNA) that helps the virus evade host immune response, thereby affecting viral pathogenesis. In addition, changes within the 3'UTR have been shown to affect transmissibility between vector and host, which can influence the development of vaccines.
Topics: 3' Untranslated Regions; 5' Untranslated Regions; Flavivirus; Virus Replication
PubMed: 28587300
DOI: 10.3390/v9060137 -
Trends in Plant Science Mar 2024Taking advantage of natural variation promotes our understanding of phenotypic diversity and trait evolution, ultimately accelerating plant breeding, in which the... (Review)
Review
Taking advantage of natural variation promotes our understanding of phenotypic diversity and trait evolution, ultimately accelerating plant breeding, in which the identification of causal variations is critical. To date, sequence variations in the coding region and transcription level polymorphisms caused by variations in the promoter have been prioritized. An upstream open reading frame (uORF) in the 5' untranslated region (5' UTR) regulates gene expression at the post-transcription or translation level. In recent years, studies have demonstrated that natural uORF variations shape phenotypic diversity. This opinion article highlights recent researches and speculates on future directions for natural uORF variation in plants.
Topics: Protein Biosynthesis; Open Reading Frames; Plant Breeding; Plants; 5' Untranslated Regions
PubMed: 37640640
DOI: 10.1016/j.tplants.2023.07.005 -
Trends in Cancer Apr 2019The 5' and 3' untranslated regions (UTRs) regulate crucial aspects of post-transcriptional gene regulation that are necessary for the maintenance of cellular... (Review)
Review
The 5' and 3' untranslated regions (UTRs) regulate crucial aspects of post-transcriptional gene regulation that are necessary for the maintenance of cellular homeostasis. When these processes go awry through mutation or misexpression of certain regulatory elements, the subsequent deregulation of oncogenic gene expression can drive or enhance cancer pathogenesis. Although the number of known cancer-related mutations in UTR regulatory elements has recently increased markedly as a result of advances in whole-genome sequencing, little is known about how the majority of these genetic aberrations contribute functionally to disease. In this review we explore the regulatory functions of UTRs, how they are co-opted in cancer, new technologies to interrogate cancerous UTRs, and potential therapeutic opportunities stemming from these regions.
Topics: 3' Untranslated Regions; 5' Untranslated Regions; Animals; Binding Sites; Gene Expression Regulation, Neoplastic; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Internal Ribosome Entry Sites; MicroRNAs; Neoplasms; Polyadenylation; Protein Biosynthesis; RNA, Messenger; Regulatory Sequences, Ribonucleic Acid; Untranslated Regions
PubMed: 30961831
DOI: 10.1016/j.trecan.2019.02.011