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Frontiers in Cellular and Infection... 2018In eukaryotic cells, the life cycle of mRNA molecules is modulated in response to environmental signals and cell-cell communication in order to support cellular... (Review)
Review
In eukaryotic cells, the life cycle of mRNA molecules is modulated in response to environmental signals and cell-cell communication in order to support cellular homeostasis. Capping, splicing and polyadenylation in the nucleus lead to the formation of transcripts that are suitable for translation in cytoplasm, until mRNA decay occurs in P-bodies. Although pre-mRNA processing and degradation mechanisms have usually been studied separately, they occur simultaneously and in a coordinated manner through protein-protein interactions, maintaining the integrity of gene expression. In the past few years, the availability of the genome sequence of , the protozoan parasite responsible for human amoebiasis, coupled to the development of the so-called "omics" technologies provided new opportunities for the study of mRNA processing and turnover in this pathogen. Here, we review the current knowledge about the molecular basis for splicing, 3' end formation and mRNA degradation in amoeba, which suggest the conservation of events related to mRNA life throughout evolution. We also present the functional characterization of some key proteins and describe some interactions that indicate the relevance of cooperative regulatory events for gene expression in this human parasite.
Topics: Amebiasis; Animals; Entamoeba histolytica; Evolution, Molecular; Humans; Polyadenylation; Protozoan Proteins; RNA Precursors; RNA Splicing; RNA Stability; RNA, Messenger
PubMed: 29971219
DOI: 10.3389/fcimb.2018.00199 -
RNA (New York, N.Y.) Apr 2015
Topics: RNA Precursors; RNA Splicing; RNA, Messenger
PubMed: 25780164
DOI: 10.1261/rna.049858.115 -
Planta May 2023Serine/arginine-rich (SR) proteins participate in RNA processing by interacting with precursor mRNAs or other splicing factors to maintain plant growth and stress... (Review)
Review
Serine/arginine-rich (SR) proteins participate in RNA processing by interacting with precursor mRNAs or other splicing factors to maintain plant growth and stress responses. Alternative splicing is an important mechanism involved in mRNA processing and regulation of gene expression at the posttranscriptional level, which is the main reason for the diversity of genes and proteins. The process of alternative splicing requires the participation of many specific splicing factors. The SR protein family is a splicing factor in eukaryotes. The vast majority of SR proteins' existence is an essential survival factor. Through its RS domain and other unique domains, SR proteins can interact with specific sequences of precursor mRNA or other splicing factors and cooperate to complete the correct selection of splicing sites or promote the formation of spliceosomes. They play essential roles in the composition and alternative splicing of precursor mRNAs, providing pivotal functions to maintain growth and stress responses in animals and plants. Although SR proteins have been identified in plants for three decades, their evolutionary trajectory, molecular function, and regulatory network remain largely unknown compared to their animal counterparts. This article reviews the current understanding of this gene family in eukaryotes and proposes potential key research priorities for future functional studies.
Topics: Animals; RNA-Binding Proteins; Serine; Nuclear Proteins; RNA Splicing; Alternative Splicing; RNA Precursors; Plant Proteins; RNA, Messenger; RNA Splicing Factors; Arginine
PubMed: 37145304
DOI: 10.1007/s00425-023-04132-0 -
Advances in Experimental Medicine and... 2017SUMO has gained prominence as a regulator in a number of cellular processes. The roles of sumoylation in RNA metabolism, however, while considerable, remain less well... (Review)
Review
SUMO has gained prominence as a regulator in a number of cellular processes. The roles of sumoylation in RNA metabolism, however, while considerable, remain less well understood. In this chapter we have assembled data from proteomic analyses, localization studies and key functional studies to extend SUMO's role to the area of mRNA processing and metabolism. Proteomic analyses have identified multiple putative sumoylation targets in complexes functioning in almost all aspects of mRNA metabolism, including capping, splicing and polyadenylation of mRNA precursors. Possible regulatory roles for SUMO have emerged in pre-mRNA 3' processing, where SUMO influences the functions of polyadenylation factors and activity of the entire complex. SUMO is also involved in regulating RNA editing and RNA binding by hnRNP proteins, and recent reports have suggested the involvement of the SUMO pathway in mRNA export. Together, these reports suggest that SUMO is involved in regulation of many aspects of mRNA metabolism and hold the promise for exciting future studies.
Topics: Animals; Heterogeneous-Nuclear Ribonucleoproteins; Humans; RNA 3' End Processing; RNA Caps; RNA Editing; RNA Precursors; RNA Processing, Post-Transcriptional; RNA Splicing; RNA, Messenger; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Transcription, Genetic
PubMed: 28197904
DOI: 10.1007/978-3-319-50044-7_2 -
Nature Reviews. Drug Discovery Feb 2020Discoveries in the past decade have highlighted the potential of mRNA as a therapeutic target for cancer. Specifically, RNA sequencing revealed that, in addition to gene... (Review)
Review
Discoveries in the past decade have highlighted the potential of mRNA as a therapeutic target for cancer. Specifically, RNA sequencing revealed that, in addition to gene mutations, alterations in mRNA can contribute to the initiation and progression of cancer. Indeed, precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3' ends by cleavage and polyadenylation, is frequently altered in tumours. These alterations result in numerous cancer-specific mRNAs that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumour-suppressor genes. Abnormally spliced and polyadenylated mRNAs are also associated with resistance to cancer treatment and, unexpectedly, certain cancers are highly sensitive to the pharmacological inhibition of splicing. This Review summarizes recent progress in our understanding of how splicing and polyadenylation are altered in cancer and highlights how this knowledge has been translated for drug discovery, resulting in the production of small molecules and oligonucleotides that modulate the spliceosome and are in clinical trials for the treatment of cancer.
Topics: Antineoplastic Agents; Humans; Molecular Targeted Therapy; Neoplasms; RNA Precursors; RNA Processing, Post-Transcriptional; RNA Splicing; RNA, Messenger
PubMed: 31554928
DOI: 10.1038/s41573-019-0042-3 -
Wiley Interdisciplinary Reviews. RNA May 2018Pre-mRNA alternative splicing is an important mechanism used to expand protein diversity in higher eukaryotes, and mutually exclusive splicing is a specific type of... (Review)
Review
Pre-mRNA alternative splicing is an important mechanism used to expand protein diversity in higher eukaryotes, and mutually exclusive splicing is a specific type of alternative splicing in which only one of the exons in a cluster is included in functional transcripts. The most extraordinary example of this is the Drosophila melanogaster Down's syndrome cell adhesion molecule gene (Dscam), which potentially encodes 38,016 different isoforms through mutually exclusive splicing. Mutually exclusive splicing is a unique and challenging model that can be used to elucidate the evolution, regulatory mechanism, and function of alternative splicing. The use of new approaches has not only greatly expanded the mutually exclusive exome, but has also enabled the systematic analyses of single-cell alternative splicing during development. Furthermore, the identification of long-range RNA secondary structures provides a mechanistic framework for the regulation of mutually exclusive splicing (i.e., Dscam splicing). This article reviews recent insights into the identification, underlying mechanism, and roles of mutually exclusive splicing. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems.
Topics: Alternative Splicing; Animals; Exons; Humans; RNA Precursors; RNA, Messenger
PubMed: 29423937
DOI: 10.1002/wrna.1468 -
The Journal of Nutrition May 2015Precursor mRNA (pre-mRNA) splicing is a critical step in gene expression that results in the removal of intronic sequences from immature mRNA, leading to the production... (Review)
Review
Precursor mRNA (pre-mRNA) splicing is a critical step in gene expression that results in the removal of intronic sequences from immature mRNA, leading to the production of mature mRNA that can be translated into protein. Alternative pre-mRNA splicing is the process whereby alternative exons and/or introns are selectively included or excluded, generating mature mRNAs that encode proteins that may differ in function. The resulting alterations in the pattern of protein isoform expression can result in changes in protein-protein interaction, subcellular localization, and flux through metabolic pathways. Although basic mechanisms of pre-mRNA splicing of introns and exons are reasonably well characterized, how these mechanisms are regulated remains poorly understood. The goal of this review is to highlight selected recent advances in our understanding of the regulation of pre-mRNA splicing by nutrients and modulation of nutrient metabolism that result from changes in pre-mRNA splicing.
Topics: Alternative Splicing; Animals; Diet; Energy Intake; Energy Metabolism; Gene Expression Regulation; Humans; Models, Biological; Protein Isoforms; Protein Transport; RNA Precursors; RNA Splicing; RNA, Messenger
PubMed: 25761502
DOI: 10.3945/jn.114.203216 -
The Journal of Biological Chemistry Sep 2023Through its role in intron cleavage, tRNA splicing endonuclease (TSEN) plays a critical function in the maturation of intron-containing pre-tRNAs. The catalytic... (Review)
Review
Through its role in intron cleavage, tRNA splicing endonuclease (TSEN) plays a critical function in the maturation of intron-containing pre-tRNAs. The catalytic mechanism and core requirement for this process is conserved between archaea and eukaryotes, but for decades, it has been known that eukaryotic TSENs have evolved additional modes of RNA recognition, which have remained poorly understood. Recent research identified new roles for eukaryotic TSEN, including processing or degradation of additional RNA substrates, and determined the first structures of pre-tRNA-bound human TSEN complexes. These recent discoveries have changed our understanding of how the eukaryotic TSEN targets and recognizes substrates. Here, we review these recent discoveries, their implications, and the new questions raised by these findings.
Topics: Humans; Introns; Nucleic Acid Conformation; RNA Precursors; RNA Splicing; RNA, Transfer; Substrate Specificity; Eukaryota; Endoribonucleases
PubMed: 37544645
DOI: 10.1016/j.jbc.2023.105138 -
Experimental & Molecular Medicine Apr 2023Cells produce multiple mRNAs through alternative splicing, which ensures proteome diversity. Because most human genes undergo alternative splicing, key components of... (Review)
Review
Cells produce multiple mRNAs through alternative splicing, which ensures proteome diversity. Because most human genes undergo alternative splicing, key components of signal transduction pathways are no exception. Cells regulate various signal transduction pathways, including those associated with cell proliferation, development, differentiation, migration, and apoptosis. Since proteins produced through alternative splicing can exhibit diverse biological functions, splicing regulatory mechanisms affect all signal transduction pathways. Studies have demonstrated that proteins generated by the selective combination of exons encoding important domains can enhance or attenuate signal transduction and can stably and precisely regulate various signal transduction pathways. However, aberrant splicing regulation via genetic mutation or abnormal expression of splicing factors negatively affects signal transduction pathways and is associated with the onset and progression of various diseases, including cancer. In this review, we describe the effects of alternative splicing regulation on major signal transduction pathways and highlight the significance of alternative splicing.
Topics: Humans; Alternative Splicing; RNA Precursors; RNA Splicing; Cell Differentiation; Proteins; Signal Transduction
PubMed: 37009804
DOI: 10.1038/s12276-023-00981-7 -
Wiley Interdisciplinary Reviews. RNA 2024Disruptions in spatiotemporal gene expression can result in atypical brain function. Specifically, autism spectrum disorder (ASD) is characterized by abnormalities in... (Review)
Review
Disruptions in spatiotemporal gene expression can result in atypical brain function. Specifically, autism spectrum disorder (ASD) is characterized by abnormalities in pre-mRNA splicing. Abnormal splicing patterns have been identified in the brains of individuals with ASD, and mutations in splicing factors have been found to contribute to neurodevelopmental delays associated with ASD. Here we review studies that shed light on the importance of splicing observed in ASD and that explored the intricate relationship between splicing factors and ASD, revealing how disruptions in pre-mRNA splicing may underlie ASD pathogenesis. We provide an overview of the research regarding all splicing factors associated with ASD and place a special emphasis on five specific splicing factors-HNRNPH2, NOVA2, WBP4, SRRM2, and RBFOX1-known to impact the splicing of ASD-related genes. In the discussion of the molecular mechanisms influenced by these splicing factors, we lay the groundwork for a deeper understanding of ASD's complex etiology. Finally, we discuss the potential benefit of unraveling the connection between splicing and ASD for the development of more precise diagnostic tools and targeted therapeutic interventions. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Evolution and Genomics > Computational Analyses of RNA RNA-Based Catalysis > RNA Catalysis in Splicing and Translation.
Topics: Humans; Autism Spectrum Disorder; Autistic Disorder; RNA Precursors; RNA Splicing; RNA Splicing Factors; Neuro-Oncological Ventral Antigen
PubMed: 38509732
DOI: 10.1002/wrna.1838