1.Emerging roles of spliceosome in cancer and immunity.
Hui YANG ; Bruce BEUTLER ; Duanwu ZHANG
Protein & Cell 2022;13(8):559-579
Precursor messenger RNA (pre-mRNA) splicing is catalyzed by an intricate ribonucleoprotein complex called the spliceosome. Although the spliceosome is considered to be general cell "housekeeping" machinery, mutations in core components of the spliceosome frequently correlate with cell- or tissue-specific phenotypes and diseases. In this review, we expound the links between spliceosome mutations, aberrant splicing, and human cancers. Remarkably, spliceosome-targeted therapies (STTs) have become efficient anti-cancer strategies for cancer patients with splicing defects. We also highlight the links between spliceosome and immune signaling. Recent studies have shown that some spliceosome gene mutations can result in immune dysregulation and notable phenotypes due to mis-splicing of immune-related genes. Furthermore, several core spliceosome components harbor splicing-independent immune functions within the cell, expanding the functional repertoire of these diverse proteins.
Humans
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Neoplasms/metabolism*
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RNA Precursors/metabolism*
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RNA Splicing
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RNA Splicing Factors/metabolism*
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Spliceosomes/metabolism*
2.Roles of alternative splicing in infectious diseases: from hosts, pathogens to their interactions.
Mengyuan LYU ; Hongli LAI ; Yili WANG ; Yanbing ZHOU ; Yi CHEN ; Dongsheng WU ; Jie CHEN ; Binwu YING
Chinese Medical Journal 2023;136(7):767-779
Alternative splicing (AS) is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs (mRNAs), extremely improving the richness of transcriptome and proteome. Both mammal hosts and pathogens require AS to maintain their life activities, and inherent physiological heterogeneity between mammals and pathogens makes them adopt different ways to perform AS. Mammals and fungi conduct a two-step transesterification reaction by spliceosomes to splice each individual mRNA (named cis -splicing). Parasites also use spliceosomes to splice, but this splicing can occur among different mRNAs (named trans -splicing). Bacteria and viruses directly hijack the host's splicing machinery to accomplish this process. Infection-related changes are reflected in the spliceosome behaviors and the characteristics of various splicing regulators (abundance, modification, distribution, movement speed, and conformation), which further radiate to alterations in the global splicing profiles. Genes with splicing changes are enriched in immune-, growth-, or metabolism-related pathways, highlighting approaches through which hosts crosstalk with pathogens. Based on these infection-specific regulators or AS events, several targeted agents have been developed to fight against pathogens. Here, we summarized recent findings in the field of infection-related splicing, including splicing mechanisms of pathogens and hosts, splicing regulation and aberrant AS events, as well as emerging targeted drugs. We aimed to systemically decode host-pathogen interactions from a perspective of splicing. We further discussed the current strategies of drug development, detection methods, analysis algorithms, and database construction, facilitating the annotation of infection-related splicing and the integration of AS with disease phenotype.
Animals
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Alternative Splicing/genetics*
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RNA Splicing
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Spliceosomes/metabolism*
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RNA, Messenger/metabolism*
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Communicable Diseases/genetics*
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Mammals/metabolism*
3.A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration.
Dawei MENG ; Qian ZHENG ; Xue ZHANG ; Xuejiao PIAO ; Li LUO ; Yichang JIA
Protein & Cell 2023;14(5):318-336
Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress. However, the underlying mechanisms of detained intron (DI) splicing are still largely unknown. Here, we suggest that post-transcriptional DI splicing is paused at the Bact state, an active spliceosome but not catalytically primed, which depends on Smad Nuclear Interacting Protein 1 (SNIP1) and RNPS1 (a serine-rich RNA binding protein) interaction. RNPS1 and Bact components preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing. Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA, a basal spliceosomal component. Snip1 conditional knockout in the cerebellum decreases DI splicing efficiency and causes neurodegeneration. Therefore, we suggest that SNIP1 and RNPS1 form a molecular brake to promote spliceosome pausing, and that its misregulation contributes to neurodegeneration.
Spliceosomes/metabolism*
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Introns/genetics*
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RNA Splicing
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RNA, Messenger/genetics*
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Cell Nucleus/metabolism*
4.A Case of Exon 7 and 8 Deletion of Survival Motor Neuron Gene in Spinal Muscular Atrophy.
Young Deuk KIM ; Jae Chul KIM ; Chi Kwan HWANG ; Kun Su LEE
Journal of the Korean Child Neurology Society 2003;11(1):163-167
Spinal muscular atrophy(SMA) is a genetic disorder of the motor neurons that cause muscular weakness and muscular atrophy due to anterior horn cell degeneration. Classic spinal muscular atrophy patient is caused by mutation in the chromosome 5(q11.2-q13.3), and the majority of the patient shows homozygous deletion of the telomeric survival motor neuron(SMN) gene in the chromosome 5. Deletion of exon 7 and 8 of the SMN gene and deletion of exon 4 and 5 of the neuronal apoptosis inhibitory protein(NAIP) are typically observed in SMA patients. The SMN protein plays a role in an essential cell metabolism process, the splicing of pre mRNA in the spliceosomes. We report a 7 month old male with SMA. He showed rapidly aggrdvatial muscular weakness and died at 7 months. His DNA analysis proved deletion of exon 7 and 8 of the telomeric copy of the SMN gene.
Anterior Horn Cells
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Apoptosis
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Chromosomes, Human, Pair 5
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DNA
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Exons*
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Humans
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Infant
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Male
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Metabolism
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Motor Neurons*
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Muscle Weakness
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Muscular Atrophy
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Muscular Atrophy, Spinal*
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Neurons
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RNA Precursors
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Spliceosomes
5.Advances in the study of SR protein family.
Genomics, Proteomics & Bioinformatics 2003;1(1):2-8
The name of SR proteins is derived from their typical RS domain that is rich in serine (Ser, S) and arginine (Arg, R). They are conserved in evolution. Up to now, 10 members of the SR protein family have been identified in humans. SR proteins contain one or two RNA binding motifs aside from the RS domain, and also possess special biochemical and immunological features. As to the functions of SR proteins, they facilitate the recruitment of the components of splicesome via protein-protein interaction to prompt the assembly of early splicesome; while in alternative splicing, tissue-specifically expressed SR protein along with the relative ratio of SR protein and heterogeneous nuclear ribonucleoprotein (hnRNP) is composed of two main regulative mechanisms to alternative splicing. Almost all of the biochemical functions are regulated by reversible phosphorylation.
Alternative Splicing
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Amino Acid Motifs
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Evolution, Molecular
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Heterogeneous-Nuclear Ribonucleoproteins
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chemistry
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Humans
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Phosphorylation
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Protein Binding
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Protein Conformation
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Protein Structure, Tertiary
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Proteomics
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methods
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RNA
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chemistry
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Spliceosomes
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chemistry
;
metabolism
6.Spliceosomal genes in the D. discoideum genome: a comparison with those in H. sapiens, D. melanogaster, A. thaliana and S. cerevisiae.
Bing YU ; Petra FEY ; Karen E KESTIN-PILCHER ; Alexei FEDOROV ; Ashwin PRAKASH ; Rex L CHISHOLM ; Jane Y WU
Protein & Cell 2011;2(5):395-409
Little is known about pre-mRNA splicing in Dictyostelium discoideum although its genome has been completely sequenced. Our analysis suggests that pre-mRNA splicing plays an important role in D. discoideum gene expression as two thirds of its genes contain at least one intron. Ongoing curation of the genome to date has revealed 40 genes in D. discoideum with clear evidence of alternative splicing, supporting the existence of alternative splicing in this unicellular organism. We identified 160 candidate U2-type spliceosomal proteins and related factors in D. discoideum based on 264 known human genes involved in splicing. Spliceosomal small ribonucleoproteins (snRNPs), PRP19 complex proteins and late-acting proteins are highly conserved in D. discoideum and throughout the metazoa. In non-snRNP and hnRNP families, D. discoideum orthologs are closer to those in A. thaliana, D. melanogaster and H. sapiens than to their counterparts in S. cerevisiae. Several splicing regulators, including SR proteins and CUG-binding proteins, were found in D. discoideum, but not in yeast. Our comprehensive catalog of spliceosomal proteins provides useful information for future studies of splicing in D. discoideum where the efficient genetic and biochemical manipulation will also further our general understanding of pre-mRNA splicing.
Alternative Splicing
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Animals
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Arabidopsis
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genetics
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Dictyostelium
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genetics
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Drosophila melanogaster
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genetics
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Genome, Protozoan
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Humans
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Phylogeny
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Ribonucleoproteins, Small Nuclear
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classification
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genetics
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Saccharomyces cerevisiae
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genetics
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Spliceosomes
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genetics
;
metabolism
7.Pseudouridines in spliceosomal snRNAs.
Andrew T YU ; Junhui GE ; Yi-Tao YU
Protein & Cell 2011;2(9):712-725
Spliceosomal RNAs are a family of small nuclear RNAs (snRNAs) that are essential for pre-mRNA splicing. All vertebrate spliceosomal snRNAs are extensively pseudouridylated after transcription. Pseudouridines in spliceosomal snRNAs are generally clustered in regions that are functionally important during splicing. Many of these modified nucleotides are conserved across species lines. Recent studies have demonstrated that spliceosomal snRNA pseudouridylation is catalyzed by two different mechanisms: an RNA-dependent mechanism and an RNA-independent mechanism. The functions of the pseudouridines in spliceosomal snRNAs (U2 snRNA in particular) have also been extensively studied. Experimental data indicate that virtually all pseudouridines in U2 snRNA are functionally important. Besides the currently known pseudouridines (constitutive modifications), recent work has also indicated that pseudouridylation can be induced at novel positions under stress conditions, thus strongly suggesting that pseudouridylation is also a regulatory modification.
Animals
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Base Sequence
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Molecular Sequence Data
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Nucleic Acid Conformation
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Nucleotides
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metabolism
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Oocytes
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cytology
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metabolism
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Pseudouridine
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metabolism
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RNA Precursors
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metabolism
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RNA Splice Sites
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RNA Splicing
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RNA, Messenger
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genetics
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metabolism
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RNA, Small Nuclear
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genetics
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metabolism
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Ribonucleoproteins, Small Nuclear
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genetics
;
metabolism
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Saccharomyces cerevisiae
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genetics
;
metabolism
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Saccharomyces cerevisiae Proteins
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genetics
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metabolism
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Spliceosomes
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genetics
;
metabolism
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Uridine
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analogs & derivatives
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metabolism
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Xenopus
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genetics
;
metabolism