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Open accessJournal ArticleDOI: 10.3389/FGENE.2021.652129

Spliceosomal snRNA Epitranscriptomics.

02 Mar 2021-Frontiers in Genetics (Frontiers Media SA)-Vol. 12, pp 652129-652129
Abstract: Small nuclear RNAs (snRNAs) are critical components of the spliceosome that catalyze the splicing of pre-mRNA. snRNAs are each complexed with many proteins to form RNA-protein complexes, termed as small nuclear ribonucleoproteins (snRNPs), in the cell nucleus. snRNPs participate in pre-mRNA splicing by recognizing the critical sequence elements present in the introns, thereby forming active spliceosomes. The recognition is achieved primarily by base-pairing interactions (or nucleotide-nucleotide contact) between snRNAs and pre-mRNA. Notably, snRNAs are extensively modified with different RNA modifications, which confer unique properties to the RNAs. Here, we review the current knowledge of the mechanisms and functions of snRNA modifications and their biological relevance in the splicing process.

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Topics: snRNP (68%), Spliceosome (65%), RNA splicing (61%) ... show more
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7 results found


Open accessJournal ArticleDOI: 10.3390/BIOMEDICINES9050550
14 May 2021-Biomedicines
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 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.

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Topics: RNA editing (64%), Antisense RNA (63%), RNA (62%) ... show more

8 Citations


Open accessJournal ArticleDOI: 10.1101/GAD.348660.121
Abstract: Spliceosomal small nuclear RNAs (snRNAs) are modified by small Cajal body (CB)-specific ribonucleoproteins (scaRNPs) to ensure snRNP biogenesis and pre-mRNA splicing. However, the function and subcellular site of snRNA modification are largely unknown. We show that CB localization of the protein Nopp140 is essential for concentration of scaRNPs in that nuclear condensate; and that phosphorylation by casein kinase 2 (CK2) at ∼80 serines targets Nopp140 to CBs. Transiting through CBs, snRNAs are apparently modified by scaRNPs. Indeed, Nopp140 knockdown-mediated release of scaRNPs from CBs severely compromises 2'-O-methylation of spliceosomal snRNAs, identifying CBs as the site of scaRNP catalysis. Additionally, alternative splicing patterns change indicating that these modifications in U1, U2, U5, and U12 snRNAs safeguard splicing fidelity. Given the importance of CK2 in this pathway, compromised splicing could underlie the mode of action of small molecule CK2 inhibitors currently considered for therapy in cholangiocarcinoma, hematological malignancies, and COVID-19.

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Topics: Cajal body (59%), SnRNP Biogenesis (59%), Small nuclear RNA (58%) ... show more

4 Citations


Open accessJournal ArticleDOI: 10.17537/2021.16.256
Abstract: The genomes of large multicellular eukaryotes mainly consist of DNA that encodes not proteins, but RNAs. The unexpected discovery of approximately the same number of protein genes in Homo sapiens and Caenorhabditis elegans led to the understanding that it is not the number of proteins that determines the complexity of the development and functioning of an organism. The phenomenon of pervasive transcription of genomes is finding more and more confirmation. Data are emerging on new types of RNA that work in different cell compartments, are expressed at different stages of development, in different tissues and perform various functions. Their main purpose is fine regulation of the main cellular processes. The presence of a rich arsenal of regulators that can interact with each other and work on the principle of interchangeability determines the physiological complexity of the organism and its ability to adapt to changing environmental conditions. An overview of the currently known functional RNAs expressed in eukaryotic genomes is presented here. There is no doubt that in the near future, using high-tech transcriptome technologies, many new RNAs will be identified and characterized. But it is likely that many of the expressed transcripts do not have a function, but are an evolutionary reserve of organisms.

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2 Citations


Open accessPosted ContentDOI: 10.1101/2021.04.29.441821
29 Apr 2021-bioRxiv
Abstract: Spliceosomal small nuclear RNAs (snRNAs) are modified by small Cajal body (CB) specific ribonucleoproteins (scaRNPs) to ensure snRNP biogenesis and pre-mRNA splicing. However, the function and subcellular site of snRNA modification are largely unknown. We show that CB localization of the protein Nopp140 is essential for concentration of scaRNPs in that nuclear condensate; and that phosphorylation by casein kinase 2 (CK2) at some 80 serines targets Nopp140 to CBs. Transiting through CBs, snRNAs are apparently modified by scaRNPs. Indeed, Nopp140 knockdown-mediated release of scaRNPs from CBs severely compromises 2'-O-methylation of spliceosomal snRNAs, identifying CBs as the site of scaRNP catalysis. Additionally, alternative splicing patterns change indicating that these modifications in U1, U2, U5, and U12 snRNAs safeguard splicing fidelity. Given the importance of CK2 in this pathway, compromised splicing could underlie the mode of action of small molecule CK2 inhibitors currently considered for therapy in cholangiocarcinoma, hematological malignancies, and COVID-19.

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Topics: Cajal body (59%), SnRNP Biogenesis (59%), RNA splicing (58%) ... show more

1 Citations


Open accessJournal ArticleDOI: 10.1002/1873-3468.14188
Ting-Yu Lin1, Rahul Mehta1, Sebastian Glatt1Institutions (1)
01 Sep 2021-FEBS Letters
Abstract: The structure, stability, and function of various coding and noncoding RNAs are influenced by chemical modifications. Pseudouridine (Ψ) is one of the most abundant post-transcriptional RNA base modifications and has been detected at individual positions in tRNAs, rRNAs, mRNAs, and snRNAs, which are referred to as Ψ-sites. By allowing formation of additional bonds with neighboring atoms, Ψ strengthens RNA-RNA and RNA-protein interactions. Although many aspects of the underlying modification reactions remain unclear, the advent of new transcriptome-wide methods to quantitatively detect Ψ-sites has recently changed our perception of the functional roles and importance of Ψ. For instance, it is now clear that the occurrence of Ψs appears to be directly linked to the lifetime and the translation efficiency of a given mRNA molecule. Furthermore, the administration of Ψ-containing RNAs reduces innate immune responses, which appears strikingly advantageous for the development of generations of mRNA-based vaccines. In this review, we aim to comprehensively summarize recent discoveries that highlight the impact of Ψ on various types of RNAs and outline possible novel biomedical applications of Ψ.

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Topics: Small nucleolar RNA (58%), Pseudouridine (51%), RNA (50%)

1 Citations


References
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145 results found


Open accessJournal ArticleDOI: 10.1016/J.CELL.2009.02.009
20 Feb 2009-Cell
Abstract: Ribonucleoproteins (RNPs) mediate key cellular functions such as gene expression and its regulation. Whereas most RNP enzymes are stable in composition and harbor preformed active sites, the spliceosome, which removes noncoding introns from precursor messenger RNAs (pre-mRNAs), follows fundamentally different strategies. In order to provide both accuracy to the recognition of reactive splice sites in the pre-mRNA and flexibility to the choice of splice sites during alternative splicing, the spliceosome exhibits exceptional compositional and structural dynamics that are exploited during substrate-dependent complex assembly, catalytic activation, and active site remodeling.

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Topics: Spliceosome (71%), Minor spliceosome (64%), RNA splicing (60%) ... show more

2,095 Citations


Open accessJournal ArticleDOI: 10.1101/CSHPERSPECT.A003707
Cindy L. Will1, Reinhard Lührmann1Institutions (1)
Abstract: Pre-mRNA splicing is catalyzed by the spliceosome, a multimegadalton ribonucleoprotein (RNP) complex comprised of five snRNPs and numerous proteins. Intricate RNA-RNA and RNP networks, which serve to align the reactive groups of the pre-mRNA for catalysis, are formed and repeatedly rearranged during spliceosome assembly and catalysis. Both the conformation and composition of the spliceosome are highly dynamic, affording the splicing machinery its accuracy and flexibility, and these remarkable dynamics are largely conserved between yeast and metazoans. Because of its dynamic and complex nature, obtaining structural information about the spliceosome represents a major challenge. Electron microscopy has revealed the general morphology of several spliceosomal complexes and their snRNP subunits, and also the spatial arrangement of some of their components. X-ray and NMR studies have provided high resolution structure information about spliceosomal proteins alone or complexed with one or more binding partners. The extensive interplay of RNA and proteins in aligning the pre-mRNA's reactive groups, and the presence of both RNA and protein at the core of the splicing machinery, suggest that the spliceosome is an RNP enzyme. However, elucidation of the precise nature of the spliceosome's active site, awaits the generation of a high-resolution structure of its RNP core.

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Topics: Spliceosome (77%), Minor spliceosome (64%), Spliceosomal complex (62%) ... show more

1,254 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.74.8.3171
Abstract: An mRNA fraction coding for hexon polypeptide, the major virion structural protein, was purified by gel electrophoresis from extracts of adenovirus 2-infected cells late in the lytic cycle. The mRNA sequences in this fraction were mapped between 51.7 and 61.3 units on the genome by visualizing RNA-DNA hybrids in the electron microscope. When hybrids of hexon mRNA and single-stranded restriction endonuclease cleavage fragments of viral DNA were visualized in the electron microscope,branched forms were observed in which 160 nucleotides of RNA from the 5' terminus were not hydrogen bonded to the single-stranded DNA. DNA sequences complementary to the RNA sequences in each 5' tail were found by electron microscopy to be located at 17, 20, and 27 units on the same strand as that coding for the body of the hexon mRNA. Thus, four segments of viral RNA may be joined together during the synthesis of mature hexon mRNA. A model is presented for adenovirus late mRNA synthesis that involves multiple splicing during maturation of a larger precursor nuclear RNA.

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Topics: RNA (59%), RNA splicing (55%), Messenger RNA (55%) ... show more

1,146 Citations


Open accessJournal ArticleDOI: 10.1016/S0092-8674(00)80925-3
06 Feb 1998-Cell
Abstract: We thank J. Thorner, J. Lorsch, and D. Herschlag for provocative discussions; J. Abelson, R. Luhrmann, T. Nilsen, and R. Reed for preprints; and G. Chanfreau, C. Collins, A. Frankel, A. Kistler, K. Lynch, S. Rader, B. Raumann, D. Ryan, C. Siebel, J. Wagner, Y. Wang, J. Wilhelm, and members of the Guthrie laboratory for critical reading of the manuscript. We are indebted to S. Korolev and G. Waksman (Washington University School of Medicine) and P. Weber (Schering-Plough Research Institute) for contributing Figure 8Figure 8. We apologize to our colleagues for work that could not be cited due to a limitation on references. Cited work from this laboratory is supported by NIH grant GM21119 to C. G. J. P. S. is supported by a California Division-American Cancer Society Fellowship #1–59–97B. C. G. is an American Cancer Society Research Professor of Molecular Genetics.

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Topics: Spliceosomal complex (51%), Prespliceosome (50%)

1,146 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2017.05.045
Ian A Roundtree1, Molly E. Evans1, Tao Pan1, Chuan He1  +1 moreInstitutions (2)
15 Jun 2017-Cell
Abstract: Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5′ cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it’s clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.

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Topics: MRNA modification (65%), MRNA methylation (60%), RNA (55%) ... show more

1,099 Citations


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