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Splicing and cancer: Challenges and opportunities

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Cancer arises from alterations in several metabolic processes affecting proliferation, growth, replication and death of cells. A fundamental challenge in the study of cancer biology is to uncover molecular mechanisms that lead to malignant cellular transformation. Recent genomic analyses revealed that many molecular alterations observed in cancers come from modifications in the splicing process, including mutations in pre‐mRNA regulatory sequences, mutations in spliceosome components, and altered ratio of specific splicing regulators. While alterations in splice site preferences might generate alternative isoforms enabling different biological functions, these might also be responsible for nonfunctional isoforms that can eventually cause dysregulation in cellular processes. Molecular characteristics of regulatory sequences and proteins might also be important prognostic tools revealing a cancer‐specific splicing pattern and linking splicing control to cancer development. The connection between cancer biology and splicing regulation is of primary importance to understand the mechanisms leading to disease and also to improve development of therapeutic approaches. Splicing modulation is being explored in new anti‐cancer therapies and further investigation of targeted splicing factors is critical for the success of these strategies. This article is categorized under: RNA Processing > Splicing Mechanisms RNA‐Based Catalysis > RNA Catalysis in Splicing and Translation RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease
Four splicing‐related proteins frequently mutated in cancers. Representation of high‐frequency mutations identified in SF3B1, ZRSR2, U2AF1, and SRSF2 (chromosomal locations are indicated below protein names). Total lengths of proteins in number of amino acids are indicated on the bottom right corner. Protein domains are shown as colored boxes: orange: PPP1R8, binding site for protein phosphatase 1 regulatory subunit 8, dark red: H1 to H11, HEAT domains 1–11, green: Zn, Zn‐finger domain, light red: RRM, RNA‐recognition motif domain, yellow: RS, arginine/serine‐rich domain, purple: UHM, U2AF‐homology motif. Mutated amino acids in each protein are represented by red circles, with the indicated substitutions. Data were retrieved from TCGA (The Cancer Genome Atlas) and Uniprot
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Splicing regulatory elements on pre‐mRNAs and alternative splicing. (a) Splicing regulatory sequences can be located on introns (intronic splicing enhancers or silencers) or exons (exonic splicing enhancers or silencers) (colored rectangles) and regulates splicing positively or negatively. These sequences are targets for SR and hnRNP proteins (diamonds). (b) Constitutive and alternative splicing possibilities. In clock‐wise orientation, besides the constitutive splicing, alternative 5′ and 3′ splice sites can be used generating different isoforms. Also, isoforms might contain an intron or part of it (retained intron), or might have skipped an exon (skipped exon). Exons might also be mutually exclusive, or activation of a cryptic splice site (yellow triangle) might occur, leading to different isoforms. Blue and pink boxes indicate constitutive sequences that always form part of mature mRNA; light green and red boxes are alternative exons; solid lines indicate introns; light pink letter “A” represents the adenosine at the branchpoint site
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Pre‐mRNA and spliceosome assembly. (a) Pre‐mRNAs are composed of exons (colored boxes) separated by the introns. Consensus splice sites at the 5′ and 3′ ends, the adenine at branchpoint site and the polypyrimidine tract (Poly‐Y tract) are shown. (b) Spliceosome is assembled upon the pre‐mRNA: the U1 snRNP binds the 5′ ss, generating E complex. U2AF protein recognizes the poly‐Y tract downstream the branchpoint site and aids U2 snRNP binding to form A complex. Bridging between U1 and U2 changes the conformation of the nascent complex and the tri‐snRNP U4/U6.U5 is recruited to form B complex. At this point, the nineteen complex (NTC, pink hexagon) joins the spliceosome. Several rearrangements lead to dissociation of U1 and U4 snRNPs and promote the formation of a catalytically active B complex (B* complex). Following that, catalytic C complex is assembled. In C complex additional rearrangements occur, promoting the second catalytic step, resulting in a post‐spliceosomal complex. As a result, exons are ligated forming the mature mRNA, introns are degraded and snRNPs are recycled
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Schematic representation of the evolutionary stages of tumor progression and alterations in splicing proteins. In the primary tumor, cells gain proliferative capabilities, reducing the activity of growth suppressors. The red square indicates a high rate of splice factors mutations. On the next stage cells gain invasive capacity, promoting angiogenesis and initiating epithelial–mesenchymal transition (EMT). This allows cells to get into blood circulation, extravasation, finally leading to distant metastasis. Cancer malignancy is represented from light to dark yellow cells; main splicing‐related proteins altered or required for each step are indicated on the upper right corner. Some of the hallmarks of cancer are also represented, which are essential characteristics for successful tumor development
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RNA in Disease and Development > RNA in Disease
RNA Processing > Splicing Regulation/Alternative Splicing
RNA-Based Catalysis > RNA Catalysis in Splicing and Translation
RNA Processing > Splicing Mechanisms

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