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RNA Biology Nov 2021U1 snRNP is one of the most abundant ribonucleoprotein (RNP) complexes in eukaryotic cells and is estimated to be approximately 1 million copies per cell. Apart from its... (Review)
Review
U1 snRNP is one of the most abundant ribonucleoprotein (RNP) complexes in eukaryotic cells and is estimated to be approximately 1 million copies per cell. Apart from its canonical role in mRNA splicing, this complex has emerged as a key regulator of eukaryotic mRNA length via inhibition of mRNA 3'-end processing at numerous intronic polyadenylation sites, in a process that is also termed 'U1 snRNP telescripting'. Several reviews have extensively described the concept of U1 telescripting and subsequently highlighted its potential impacts in mRNA metabolism. Here, we review what is currently known regarding the underlying mechanisms of this important phenomenon and discuss open questions and future challenges.
Topics: Animals; Humans; Polyadenylation; RNA Precursors; RNA Splicing; RNA, Messenger; Ribonucleoprotein, U1 Small Nuclear
PubMed: 33416026
DOI: 10.1080/15476286.2021.1872963 -
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 -
Cell Reports Dec 2023Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are...
Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are required for miRNA activity. We generate Ago1, Ago3, and Ago4-deficient mice (Ago134) and find AGO1/3/4 to be redundant for miRNA biogenesis, homeostasis, or function, a role that is carried out by AGO2. Instead, AGO1/3/4 regulate the expansion of type 2 immunity via precursor mRNA splicing in CD4 T helper (Th) lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing, and in particular the isoforms of the gene Nisch, resulting in a dysregulated Nisch isoform ratio. This work uncouples AGO1, AGO3, and AGO4 from miRNA-mediated RNA interference, identifies an AGO3:SF3B3 complex in the nucleus, and reveals a mechanism by which AGO proteins regulate inflammatory diseases.
Topics: Animals; Mice; Argonaute Proteins; Imidazoline Receptors; Mammals; MicroRNAs; RNA Interference; RNA Precursors; RNA Splicing; RNA, Messenger
PubMed: 38096048
DOI: 10.1016/j.celrep.2023.113515 -
RNA (New York, N.Y.) Apr 2015
Topics: RNA Precursors; RNA Splicing; RNA, Messenger
PubMed: 25780164
DOI: 10.1261/rna.049858.115 -
Genes Oct 2023Since the discovery of RNA splicing as a fundamental step to remove introns from pre-mRNA to produce mature mRNAs, substantial research in the past decades has...
Since the discovery of RNA splicing as a fundamental step to remove introns from pre-mRNA to produce mature mRNAs, substantial research in the past decades has highlighted RNA splicing as a critical mediator of gene expression and proteome diversity, also being important in many developmental and biological processes [...].
Topics: Humans; RNA Splicing; RNA Precursors; Neoplasms; RNA, Messenger; Introns
PubMed: 38002963
DOI: 10.3390/genes14112020 -
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 -
Biophysical Journal Feb 2022Nascent pre-mRNA 3'-end cleavage and polyadenylation (C/P) involves numerous proteins that recognize multiple RNA elements. Human CSTF2 binds to a downstream U- or...
Nascent pre-mRNA 3'-end cleavage and polyadenylation (C/P) involves numerous proteins that recognize multiple RNA elements. Human CSTF2 binds to a downstream U- or G/U-rich sequence through its RNA recognition motif (RRM) regulating C/P. We previously reported the only known disease-related CSTF2 RRM mutant (CSTF2) and showed that it changed the on-rate of RNA binding, leading to alternative polyadenylation in brains of mice carrying the same mutation. In this study, we further investigated the role of electrostatic interactions in the thermodynamics and kinetics of RNA binding for the CSTF2 RRM and the downstream consequences for regulation of C/P. By combining mutagenesis with NMR spectroscopy and biophysical assays, we confirmed that electrostatic attraction is the dominant factor in RRM binding to a naturally occurring U-rich RNA sequence. Moreover, we demonstrate that RNA binding is accompanied by an enthalpy-entropy compensation mechanism that is supported by changes in pico-to-nanosecond timescale RRM protein dynamics. We suggest that the dynamic binding of the RRM to U-rich RNA supports the diversity of sequences it encounters in the nucleus. Lastly, in vivo C/P assays demonstrate a competition between fast, high affinity RNA binding and efficient, correct C/P. These results highlight the importance of the surface charge of the RRM in RNA binding and the balance between nascent mRNA binding and C/P in vivo.
Topics: Animals; Mice; Polyadenylation; Protein Binding; RNA; RNA Precursors; RNA Recognition Motif; Static Electricity
PubMed: 35090899
DOI: 10.1016/j.bpj.2022.01.005 -
Genomics Sep 2020MicroRNAs (miRNAs) are small endogenous non-coding RNAs in eukaryotes which regulate the expression of numerous genes post-transcriptionally, thereby playing critical... (Review)
Review
MicroRNAs (miRNAs) are small endogenous non-coding RNAs in eukaryotes which regulate the expression of numerous genes post-transcriptionally, thereby playing critical roles in cells and organismal development. The high-throughput sequencing technologies enable the effective detection and annotation of miRNAs. Several miRNA variants with heterogeneous ends, lengths, and sequences can be generated from a single miRNA locus. Discovery of these miRNA variants, also known as miRNA isoforms or isomiRs, has made our understanding of the cells' miRNome deeper than previously pictured. Despite their wide presence in multiple datasets, the different possible origins and true biological significance of isomiRs are yet to be uncovered. Several recent emerging studies suggest that isomiRs are biologically active and non-randomly formed. This review aims to provide a comprehensive insight into the origins and biological importance of isomiRs, highlighting the enormous complexity of miRNA regulatory networks which broadens our knowledge about the post-transcriptional gene regulation in plants.
Topics: MicroRNAs; Plant Proteins; RNA Editing; RNA Precursors; RNA, Plant; Ribonuclease III
PubMed: 32561347
DOI: 10.1016/j.ygeno.2020.06.019 -
RNA Biology Jan 2013In eukaryotic cells, introns are spliced from pre-mRNAs by the spliceosome. Both the composition and the structure of the spliceosome are highly dynamic, and eight... (Review)
Review
In eukaryotic cells, introns are spliced from pre-mRNAs by the spliceosome. Both the composition and the structure of the spliceosome are highly dynamic, and eight DExD/H RNA helicases play essential roles in controlling conformational rearrangements. There is evidence that the various helicases are functionally and physically connected with each other and with many other factors in the spliceosome. Understanding the dynamics of those interactions is essential to comprehend the mechanism and regulation of normal as well as of pathological splicing. This review focuses on recent advances in the characterization of the splicing helicases and their interactions, and highlights the deep integration of splicing helicases in global mRNP biogenesis pathways.
Topics: RNA Helicases; RNA Precursors; RNA Processing, Post-Transcriptional; RNA Splicing; Spliceosomes
PubMed: 23229095
DOI: 10.4161/rna.22547