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Journal of Medical Genetics Oct 2005Variations in new splicing regulatory elements are difficult to identify exclusively by sequence inspection and may result in deleterious effects on precursor (pre) mRNA... (Review)
Review
Variations in new splicing regulatory elements are difficult to identify exclusively by sequence inspection and may result in deleterious effects on precursor (pre) mRNA splicing. These mutations can result in either complete skipping of the exon, retention of the intron, or the introduction of a new splice site within an exon or intron. Sometimes mutations that do not disrupt or create a splice site activate pre-existing pseudo splice sites, consistent with the proposal that introns contain splicing inhibitory sequences. These variants can also affect the fine balance of isoforms produced by alternatively spliced exons and in consequence cause disease. Available genomic pathology data reveal that we are still partly ignorant of the basic mechanisms that underlie the pre-mRNA splicing process. The fact that human pathology can provide pointers to new modulatory elements of splicing should be exploited.
Topics: Alternative Splicing; Base Sequence; Binding Sites; Exons; Genetic Predisposition to Disease; Humans; Introns; Models, Genetic; Molecular Sequence Data; Mutation; Protein Isoforms; RNA Precursors; RNA Splicing; RNA, Messenger
PubMed: 16199547
DOI: 10.1136/jmg.2004.029538 -
Annual Review of Biochemistry 2015Precursor messenger RNA (pre-mRNA) splicing is a critical step in the posttranscriptional regulation of gene expression, providing significant expansion of the... (Review)
Review
Precursor messenger RNA (pre-mRNA) splicing is a critical step in the posttranscriptional regulation of gene expression, providing significant expansion of the functional proteome of eukaryotic organisms with limited gene numbers. Split eukaryotic genes contain intervening sequences or introns disrupting protein-coding exons, and intron removal occurs by repeated assembly of a large and highly dynamic ribonucleoprotein complex termed the spliceosome, which is composed of five small nuclear ribonucleoprotein particles, U1, U2, U4/U6, and U5. Biochemical studies over the past 10 years have allowed the isolation as well as compositional, functional, and structural analysis of splicing complexes at distinct stages along the spliceosome cycle. The average human gene contains eight exons and seven introns, producing an average of three or more alternatively spliced mRNA isoforms. Recent high-throughput sequencing studies indicate that 100% of human genes produce at least two alternative mRNA isoforms. Mechanisms of alternative splicing include RNA-protein interactions of splicing factors with regulatory sites termed silencers or enhancers, RNA-RNA base-pairing interactions, or chromatin-based effects that can change or determine splicing patterns. Disease-causing mutations can often occur in splice sites near intron borders or in exonic or intronic RNA regulatory silencer or enhancer elements, as well as in genes that encode splicing factors. Together, these studies provide mechanistic insights into how spliceosome assembly, dynamics, and catalysis occur; how alternative splicing is regulated and evolves; and how splicing can be disrupted by cis- and trans-acting mutations leading to disease states. These findings make the spliceosome an attractive new target for small-molecule, antisense, and genome-editing therapeutic interventions.
Topics: Alternative Splicing; Animals; Disease; Gene Expression Regulation; Humans; Mutation; RNA Precursors; RNA Splicing; RNA, Catalytic; Ribonucleoproteins, Small Nuclear; Spliceosomes
PubMed: 25784052
DOI: 10.1146/annurev-biochem-060614-034316 -
RNA (New York, N.Y.) Jan 2019MicroRNAs (miRNAs) are important regulators of gene expression that bind complementary target mRNAs and repress their expression. Precursor miRNA molecules undergo... (Review)
Review
MicroRNAs (miRNAs) are important regulators of gene expression that bind complementary target mRNAs and repress their expression. Precursor miRNA molecules undergo nuclear and cytoplasmic processing events, carried out by the endoribonucleases DROSHA and DICER, respectively, to produce mature miRNAs that are loaded onto the RISC (RNA-induced silencing complex) to exert their biological function. Regulation of mature miRNA levels is critical in development, differentiation, and disease, as demonstrated by multiple levels of control during their biogenesis cascade. Here, we will focus on post-transcriptional mechanisms and will discuss the impact of -acting sequences in precursor miRNAs, as well as -acting factors that bind to these precursors and influence their processing. In particular, we will highlight the role of general RNA-binding proteins (RBPs) as factors that control the processing of specific miRNAs, revealing a complex layer of regulation in miRNA production and function.
Topics: Animals; Cell Nucleus; Cytoplasm; Genetic Variation; Humans; MicroRNAs; RNA Precursors; RNA Processing, Post-Transcriptional; RNA-Binding Proteins; RNA-Induced Silencing Complex; Ribonuclease III
PubMed: 30333195
DOI: 10.1261/rna.068692.118 -
Nature Reviews. Molecular Cell Biology Jan 2017Alternative polyadenylation (APA) is an RNA-processing mechanism that generates distinct 3' termini on mRNAs and other RNA polymerase II transcripts. It is widespread... (Review)
Review
Alternative polyadenylation (APA) is an RNA-processing mechanism that generates distinct 3' termini on mRNAs and other RNA polymerase II transcripts. It is widespread across all eukaryotic species and is recognized as a major mechanism of gene regulation. APA exhibits tissue specificity and is important for cell proliferation and differentiation. In this Review, we discuss the roles of APA in diverse cellular processes, including mRNA metabolism, protein diversification and protein localization, and more generally in gene regulation. We also discuss the molecular mechanisms underlying APA, such as variation in the concentration of core processing factors and RNA-binding proteins, as well as transcription-based regulation.
Topics: 3' Untranslated Regions; Active Transport, Cell Nucleus; Exons; Gene Expression Regulation; Humans; Polyadenylation; RNA Precursors; RNA Stability; RNA, Messenger; RNA-Binding Proteins; Ribonucleoprotein, U1 Small Nuclear
PubMed: 27677860
DOI: 10.1038/nrm.2016.116 -
RNA Biology Jan 2023Precursor mRNA (pre-mRNA) splicing is an essential step in human gene expression and is carried out by a large macromolecular machine called the spliceosome. Given the... (Review)
Review
Precursor mRNA (pre-mRNA) splicing is an essential step in human gene expression and is carried out by a large macromolecular machine called the spliceosome. Given the spliceosome's role in shaping the cellular transcriptome, it is not surprising that mutations in the splicing machinery can result in a range of human diseases and disorders (spliceosomopathies). This review serves as an introduction into the main features of the pre-mRNA splicing machinery in humans and how changes in the function of its components can lead to diseases ranging from blindness to cancers. Recently, several drugs have been developed that interact directly with this machinery to change splicing outcomes at either the single gene or transcriptome-scale. We discuss the mechanism of action of several drugs that perturb splicing in unique ways. Finally, we speculate on what the future may hold in the emerging area of spliceosomopathies and spliceosome-targeted treatments.
Topics: Humans; RNA Precursors; RNA Splicing; Spliceosomes; Neoplasms
PubMed: 37528617
DOI: 10.1080/15476286.2023.2239601 -
The FEBS Journal Jul 2022Coordination of transcription and processing of RNA is a basic principle in regulation of gene expression in eukaryotes. In the case of mRNA, coordination is primarily... (Review)
Review
Coordination of transcription and processing of RNA is a basic principle in regulation of gene expression in eukaryotes. In the case of mRNA, coordination is primarily founded on a co-transcriptional processing mechanism by which a nascent precursor mRNA undergoes maturation via cleavage and modification by the transcription machinery. A similar mechanism controls the biosynthesis of rRNA. However, the coordination of transcription and processing of tRNA, a rather short transcript, remains unknown. Here, we present a model for high molecular weight initiation complexes of human RNA polymerase III that assemble on tRNA genes and process precursor transcripts to mature forms. These multifunctional initiation complexes may support co-transcriptional processing, such as the removal of the 5' leader of precursor tRNA by RNase P. Based on this model, maturation of tRNA is predetermined prior to transcription initiation.
Topics: Humans; RNA Polymerase III; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Transfer; Ribonuclease P; Transcription, Genetic
PubMed: 33929081
DOI: 10.1111/febs.15904 -
Current Opinion in Plant Biology Oct 2021Light signal perceived by the red/far-red absorbing phytochrome (phy) family of photoreceptors regulates plant growth and development throughout the life cycle.... (Review)
Review
Light signal perceived by the red/far-red absorbing phytochrome (phy) family of photoreceptors regulates plant growth and development throughout the life cycle. Phytochromes regulate the light-triggered physiological responses by controlling gene expression both at the transcriptional and post-transcriptional levels. Recent large-scale RNA-seq studies have demonstrated the roles of phys in altering the global transcript diversity by modulating the pre-mRNA splicing in response to light. Moreover, several phy-interacting splicing factors/regulators from different species have been identified using forward genetics and protein-protein interaction studies, which modulate the light-regulated pre-mRNA splicing. In this article, we summarize our current understanding of the role of phys in the light-mediated pre-mRNA splicing and how that contributes to the regulation of gene expression to promote photomorphogenesis.
Topics: Arabidopsis; Arabidopsis Proteins; Light; Phytochrome; RNA Precursors; RNA Splicing
PubMed: 33823333
DOI: 10.1016/j.pbi.2021.102037 -
Trends in Cell Biology Jun 2011Alternative splicing is a process to differentially link exon regions in a single precursor mRNA to produce two or more different mature mRNAs, a strategy frequently... (Review)
Review
Alternative splicing is a process to differentially link exon regions in a single precursor mRNA to produce two or more different mature mRNAs, a strategy frequently used by higher eukaryotic cells to increase proteome diversity and/or enable additional post-transcriptional control of gene expression. This process can take place either co-transcriptionally or post-transcriptionally. When and where RNA splicing takes place in the cell represents a central question of cell biology; co-transcriptional splicing allows functional integration of transcription and RNA processing machineries, and could allow them to modulate one another, whereas post-transcriptional splicing could facilitate coupling RNA splicing with downstream events such as RNA export to create additional layers for regulated gene expression. This review focuses on recent advances in co- and post-transcriptional RNA splicing and proposes a new paradigm that some specific coupling events contribute to genome organization in higher eukaryotic cells.
Topics: Animals; Biocatalysis; Cell Nucleus; Genome; Humans; RNA Precursors; RNA Splicing; Transcription, Genetic
PubMed: 21514162
DOI: 10.1016/j.tcb.2011.03.003 -
Methods (San Diego, Calif.) Aug 2017Crystallography is a powerful tool to determine the atomic structures of proteins and RNAs. X-ray crystallography has been used to determine the structure of many... (Review)
Review
Crystallography is a powerful tool to determine the atomic structures of proteins and RNAs. X-ray crystallography has been used to determine the structure of many splicing related proteins and RNAs, making major contributions to our understanding of the molecular mechanism and regulation of pre-mRNA splicing. Compared to other structural methods, crystallography has its own advantage in the high-resolution structural information it can provide and the unique biological questions it can answer. In addition, two new crystallographic methods - the serial femtosecond crystallography and 3D electron crystallography - were developed to overcome some of the limitations of traditional X-ray crystallography and broaden the range of biological problems that crystallography can solve. This review discusses the theoretical basis, instrument requirements, troubleshooting, and exciting potential of these crystallographic methods to further our understanding of pre-mRNA splicing, a critical event in gene expression of all eukaryotes.
Topics: Crystallography, X-Ray; Microscopy, Electron, Transmission; Nanoparticles; Nucleic Acid Conformation; RNA Precursors; RNA Splicing
PubMed: 28506657
DOI: 10.1016/j.ymeth.2017.04.023 -
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