scispace - formally typeset
Search or ask a question
Journal ArticleDOI

The Spliceosome: Design Principles of a Dynamic RNP Machine

20 Feb 2009-Cell (Cell Press)-Vol. 136, Iss: 4, pp 701-718
TL;DR: The spliceosome exhibits exceptional compositional and structural dynamics that are exploited during substrate-dependent complex assembly, catalytic activation, and active site remodeling in the pre-mRNAs.
About: This article is published in Cell.The article was published on 2009-02-20 and is currently open access. It has received 2316 citations till now. The article focuses on the topics: Spliceosome & Minor spliceosome.
Citations
More filters
Journal ArticleDOI
TL;DR: The function of lncRNAs in developmental processes, such as in dosage compensation, genomic imprinting, cell differentiation and organogenesis, with a particular emphasis on mammalian development are described.
Abstract: Genomes of multicellular organisms are characterized by the pervasive expression of different types of non-coding RNAs (ncRNAs). Long ncRNAs (lncRNAs) belong to a novel heterogeneous class of ncRNAs that includes thousands of different species. lncRNAs have crucial roles in gene expression control during both developmental and differentiation processes, and the number of lncRNA species increases in genomes of developmentally complex organisms, which highlights the importance of RNA-based levels of control in the evolution of multicellular organisms. In this Review, we describe the function of lncRNAs in developmental processes, such as in dosage compensation, genomic imprinting, cell differentiation and organogenesis, with a particular emphasis on mammalian development.

2,464 citations

Journal ArticleDOI
27 Mar 2014-Cell
TL;DR: The pathway of ncRNA research is described, where every established "rule" seems destined to be overturned.

1,875 citations


Cites background from "The Spliceosome: Design Principles ..."

  • ...…proteins to form the spliceosome, which undergoes a dynamic series of ordered (and reversible) conformational alterations and protein exchanges (Hoskins and Moore, 2012; Wahl et al., 2009), leading to the first and second steps of splicing and ultimate release of the lariat intron and spliced RNA....

    [...]

  • ...The snRNPs assemble on an intron along with a host of proteins to form the spliceosome, which undergoes a dynamic series of ordered (and reversible) conformational alterations and protein exchanges (Hoskins and Moore, 2012; Wahl et al., 2009), leading to the first and second steps of splicing and ultimate release of the lariat intron and spliced RNA....

    [...]

Journal ArticleDOI
06 Oct 2011-Nature
TL;DR: The results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.
Abstract: Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (∼45 to ∼85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.

1,746 citations

Journal ArticleDOI
TL;DR: This work presents a census of 1,542 manually curated RBPs that are analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression, a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.
Abstract: Post-transcriptional gene regulation (PTGR) concerns processes involved in the maturation, transport, stability and translation of coding and non-coding RNAs. RNA-binding proteins (RBPs) and ribonucleoproteins coordinate RNA processing and PTGR. The introduction of large-scale quantitative methods, such as next-generation sequencing and modern protein mass spectrometry, has renewed interest in the investigation of PTGR and the protein factors involved at a systems-biology level. Here, we present a census of 1,542 manually curated RBPs that we have analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression. Our analysis is a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.

1,479 citations

Journal ArticleDOI
TL;DR: 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, but elucidation of the precise nature of its active site awaits the generation of a high-resolution structure of its RNP core.
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.

1,436 citations


Cites background from "The Spliceosome: Design Principles ..."

  • ...As the U6 snRNA appears to have lost most of its preactivation binding partners, it not only engages in novel base pairing interactions with U2 but also new protein–RNA interactions are thought to be established (Wahl et al. 2009)....

    [...]

  • ...Cite as Cold Spring Harb Perspect Biol 2011;3:a003707 9 are loosely associated and/or have redundant functions (e.g., different SR-proteins) and thus are likely not required to splice every pre-mRNA substrate (Wahl et al. 2009)....

    [...]

  • ...pairing interactions with U2 but also new protein–RNA interactions are thought to be established (Wahl et al. 2009)....

    [...]

  • ...A dramatic exchange of proteins occurs during spliceosome assembly and activation (Wahl et al. 2009)....

    [...]

  • ..., different SR-proteins) and thus are likely not required to splice every pre-mRNA substrate (Wahl et al. 2009)....

    [...]

References
More filters
Journal ArticleDOI
TL;DR: Many gene sequences in eukaryotic genomes encode entire proteins or large segments of proteins that lack a well-structured three-dimensional fold, whereas others constitute flexible linkers that have a role in the assembly of macromolecular arrays.
Abstract: Many gene sequences in eukaryotic genomes encode entire proteins or large segments of proteins that lack a well-structured three-dimensional fold. Disordered regions can be highly conserved between species in both composition and sequence and, contrary to the traditional view that protein function equates with a stable three-dimensional structure, disordered regions are often functional, in ways that we are only beginning to discover. Many disordered segments fold on binding to their biological targets (coupled folding and binding), whereas others constitute flexible linkers that have a role in the assembly of macromolecular arrays.

3,599 citations


"The Spliceosome: Design Principles ..." refers background in this paper

  • ...…a large number o proteins that are either natively disordered (intrinsically unstruc tured proteins, IUPs) or bear sizeable regions that lack stable tertiary structure (intrinsically unstructured regions, IURs) do not follow this structure-function paradigm (reviewed in Dyson and Wright, 2005)....

    [...]

Journal ArticleDOI
TL;DR: This review describes what is currently known of the molecular mechanisms that control changes in splice site choice and starts with the best-characterized systems from the Drosophila sex determination pathway, and then describes the regulators of other systems about whose mechanisms there is some data.
Abstract: Alternative pre-mRNA splicing is a central mode of genetic regulation in higher eukaryotes. Variability in splicing patterns is a major source of protein diversity from the genome. In this review, I describe what is currently known of the molecular mechanisms that control changes in splice site choice. I start with the best-characterized systems from the Drosophila sex determination pathway, and then describe the regulators of other systems about whose mechanisms there is some data. How these regulators are combined into complex systems of tissue-specific splicing is discussed. In conclusion, very recent studies are presented that point to new directions for understanding alternative splicing and its mechanisms.

2,590 citations


"The Spliceosome: Design Principles ..." refers background in this paper

  • ...The SR protein ASF/SF2 and hnRNP A1 are a well-characterized example of factors that exhibit antagonistic effects (Black, 2003; Caceres et al., 1994; Zhu et al., 2001)....

    [...]

  • ...…spliced, that is, they are present in every mRNA produced from a given pre-mRNA, many are alternatively spliced (especially in higher eukaryotes) to generate variable forms of mRNA from a single pre-mRNA species (reviewed in Black, 2003; Blencowe, 2006; Graveley, 2001; Smith and Valcarcel, 2000)....

    [...]

Journal ArticleDOI
TL;DR: As the splicing mechanisms that depend on exonic signals are elucidated, new therapeutic approaches to treating certain genetic diseases can begin to be explored.
Abstract: Point mutations in the coding regions of genes are commonly assumed to exert their effects by altering single amino acids in the encoded proteins. However, there is increasing evidence that many human disease genes harbour exonic mutations that affect pre-mRNA splicing. Nonsense, missense and even translationally silent mutations can inactivate genes by inducing the splicing machinery to skip the mutant exons. Similarly, coding-region single-nucleotide polymorphisms might cause phenotypic variability by influencing splicing accuracy or efficiency. As the splicing mechanisms that depend on exonic signals are elucidated, new therapeutic approaches to treating certain genetic diseases can begin to be explored.

2,218 citations


"The Spliceosome: Design Principles ..." refers background in this paper

  • ...Recognition and selection of splice sites is in most cases influenced by flanking pre-mRNA regulatory sequences—so-called intronic and exonic splicing enhancers or silencers—that can have positive or negative effects on splice-site usage (Cartegni et al., 2002; Singh and Valcarcel, 2005)....

    [...]

Journal Article
01 Jan 1986-Nature

1,981 citations

Journal ArticleDOI
TL;DR: 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, but elucidation of the precise nature of its active site awaits the generation of a high-resolution structure of its RNP core.
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.

1,436 citations


"The Spliceosome: Design Principles ..." refers background in this paper

  • ..., 2002), have led to the hypothesis that the spliceosome can also exist in a more extensively preassembled form selection, and glycerol gradient centrifugation), landmark assembly intermediates are operationally defined by the sequential association and release of the spliceosomal snRNPs (reviewed in Brow, 2002; Will and Lührmann, 2006)....

    [...]

  • ...…the spliceosome can also exist in a more extensively preassembled form selection, and glycerol gradient centrifugation), landmark assembly intermediates are operationally defined by the sequential association and release of the spliceosomal snRNPs (reviewed in Brow, 2002; Will and Lührmann, 2006)....

    [...]