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Results: 1 to 10 of 12

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Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types.
Seiler M, Peng S, Agrawal AA, Palacino J, Teng T, Zhu P, Smith PG, Cancer Genome Atlas Research Network, Buonamici S, Yu L
(2018) Cell Rep 23: 282-296.e4
MeSH Terms: Cell Line, Tumor, Genes, Tumor Suppressor, Humans, Loss of Function Mutation, Mutation Rate, Neoplasms, Oncogenes, RNA Splicing, RNA Splicing Factors
Show Abstract · Added October 30, 2019
Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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1 Members
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MeSH Terms
Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure.
He KY, Wang H, Cade BE, Nandakumar P, Giri A, Ware EB, Haessler J, Liang J, Smith JA, Franceschini N, Le TH, Kooperberg C, Edwards TL, Kardia SL, Lin X, Chakravarti A, Redline S, Zhu X
(2017) PLoS Genet 13: e1006678
MeSH Terms: Adult, Blood Pressure, Body Mass Index, Chromosomes, Human, Pair 16, European Continental Ancestry Group, Family Health, Female, Gene Expression, Gene Frequency, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, RNA Splicing Factors
Show Abstract · Added April 26, 2017
Many large genome-wide association studies (GWAS) have identified common blood pressure (BP) variants. However, most of the identified BP variants do not overlap with the linkage evidence observed from family studies. We thus hypothesize that multiple rare variants contribute to the observed linkage evidence. We performed linkage analysis using 517 individuals in 130 European families from the Cleveland Family Study (CFS) who have been genotyped on the Illumina OmniExpress Exome array. The largest linkage peak was observed on chromosome 16p13 (MLOD = 2.81) for systolic blood pressure (SBP). Follow-up conditional linkage and association analyses in the linkage region identified multiple rare, coding variants in RBFOX1 associated with reduced SBP. In a 17-member CFS family, carriers of the missense variant rs149974858 are normotensive despite being obese (average BMI = 60 kg/m2). Gene-based association test of rare variants using SKAT-O showed significant association with SBP (p-value = 0.00403) and DBP (p-value = 0.0258) in the CFS participants and the association was replicated in large independent replication studies (N = 57,234, p-value = 0.013 for SBP, 0.0023 for PP). RBFOX1 is expressed in brain tissues, the atrial appendage and left ventricle in the heart, and in skeletal muscle tissues, organs/tissues which are potentially related to blood pressure. Our study showed that associations of rare variants could be efficiently detected using family information.
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19 MeSH Terms
Comparative analysis of the GNAQ, GNA11, SF3B1, and EIF1AX driver mutations in melanoma and across the cancer spectrum.
Johnson DB, Roszik J, Shoushtari AN, Eroglu Z, Balko JM, Higham C, Puzanov I, Patel SP, Sosman JA, Woodman SE
(2016) Pigment Cell Melanoma Res 29: 470-3
MeSH Terms: Eukaryotic Initiation Factor-1, GTP-Binding Protein alpha Subunits, GTP-Binding Protein alpha Subunits, Gq-G11, Genes, Neoplasm, Humans, Immunotherapy, Melanoma, Mutation, Mutation, Missense, Neoplasms, Phosphoproteins, Point Mutation, Prognosis, RNA Splicing Factors
Added April 6, 2017
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1 Members
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14 MeSH Terms
Systematic two-hybrid and comparative proteomic analyses reveal novel yeast pre-mRNA splicing factors connected to Prp19.
Ren L, McLean JR, Hazbun TR, Fields S, Vander Kooi C, Ohi MD, Gould KL
(2011) PLoS One 6: e16719
MeSH Terms: Models, Biological, Organisms, Genetically Modified, Protein Binding, Protein Structure, Tertiary, Proteomics, RNA Precursors, RNA Splicing, RNA Splicing Factors, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Schizosaccharomyces, Spliceosomes, Transcription Factors, Two-Hybrid System Techniques, Yeasts
Show Abstract · Added March 5, 2014
Prp19 is the founding member of the NineTeen Complex, or NTC, which is a spliceosomal subcomplex essential for spliceosome activation. To define Prp19 connectivity and dynamic protein interactions within the spliceosome, we systematically queried the Saccharomyces cerevisiae proteome for Prp19 WD40 domain interaction partners by two-hybrid analysis. We report that in addition to S. cerevisiae Cwc2, the splicing factor Prp17 binds directly to the Prp19 WD40 domain in a 1:1 ratio. Prp17 binds simultaneously with Cwc2 indicating that it is part of the core NTC complex. We also find that the previously uncharacterized protein Urn1 (Dre4 in Schizosaccharomyces pombe) directly interacts with Prp19, and that Dre4 is conditionally required for pre-mRNA splicing in S. pombe. S. pombe Dre4 and S. cerevisiae Urn1 co-purify U2, U5, and U6 snRNAs and multiple splicing factors, and dre4Δ and urn1Δ strains display numerous negative genetic interactions with known splicing mutants. The S. pombe Prp19-containing Dre4 complex co-purifies three previously uncharacterized proteins that participate in pre-mRNA splicing, likely before spliceosome activation. Our multi-faceted approach has revealed new low abundance splicing factors connected to NTC function, provides evidence for distinct Prp19 containing complexes, and underscores the role of the Prp19 WD40 domain as a splicing scaffold.
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3 Members
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15 MeSH Terms
Genetic modifiers of neurological disease.
Kearney JA
(2011) Curr Opin Genet Dev 21: 349-53
MeSH Terms: Animals, Carrier Proteins, Charcot-Marie-Tooth Disease, Disease Models, Animal, Humans, Huntington Disease, Mice, Nervous System Diseases, Phenotype, RNA Splicing Factors, Rett Syndrome, Spinocerebellar Ataxias
Show Abstract · Added May 27, 2014
Genetic modifiers make an important contribution to neurological disease phenotypes. Significant progress has been made by studying genetic modifiers in model organisms. The ability to study complex genetic interactions in model systems contributes to our understanding of the genetic factors that influence neurological disease. This will lead to the development of novel therapeutic strategies and personalized treatment based on genetic risk.
Copyright © 2010 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
Sex-specific roles of beta-catenin in mouse gonadal development.
Liu CF, Bingham N, Parker K, Yao HH
(2009) Hum Mol Genet 18: 405-17
MeSH Terms: Animals, DNA-Binding Proteins, Female, Gene Expression Regulation, Developmental, Gonads, Male, Mice, Mice, Transgenic, RNA Splicing Factors, Sex Differentiation, Signal Transduction, Species Specificity, Transcription Factors, beta Catenin
Show Abstract · Added October 13, 2015
Sexually dimorphic development of the gonads is controlled by positive and negative regulators produced by somatic cells. Many Wnt ligands, including ones that signal via the canonical beta-catenin pathway, are expressed in fetal gonads. beta-catenin, a key transcriptional regulator of the canonical Wnt pathway and an element of the cell adhesion complex, is essential for various aspects of embryogenesis. To study the involvement of beta-catenin in sex determination, we ablated beta-catenin specifically in the SF1-positive population of somatic cells. Although beta-catenin was present in gonads of both sexes, it was necessary only for ovarian differentiation but dispensable for testis development. Loss of beta-catenin in fetal testes did not affect Sertoli cell differentiation, testis morphogenesis or masculinization of the embryos. However, we observed molecular and morphological defects in ovaries lacking beta-catenin, including formation of testis-specific coelomic vessel, appearance of androgen-producing adrenal-like cells and loss of female germ cells. These phenotypes were strikingly similar to those found in the R-spondin1 (Rspo1) and Wnt4 knockout ovaries. In the absence of beta-catenin, expression of Wnt4 was down-regulated while that of Rspo1 was not affected, placing beta-catenin as a component in between Rspo1 and Wnt4. Our results demonstrate that beta-catenin is responsible for transducing sex-specific signals in the SF1-positive somatic cell population during mouse gonadal development.
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14 MeSH Terms
Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1.
Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE, Orr HT, Zoghbi HY
(2008) Nature 452: 713-8
MeSH Terms: Alleles, Animals, Ataxin-1, Ataxins, Drosophila Proteins, Drosophila melanogaster, Humans, Mice, Multiprotein Complexes, Nerve Tissue Proteins, Nuclear Proteins, Open Reading Frames, Peptides, Protein Binding, Protein Structure, Quaternary, Purkinje Cells, RNA Splicing Factors, RNA-Binding Proteins, Repressor Proteins, Ribonucleoprotein, U2 Small Nuclear, Spinocerebellar Ataxias, Trinucleotide Repeat Expansion, Two-Hybrid System Techniques
Show Abstract · Added April 7, 2010
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.
1 Communities
1 Members
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23 MeSH Terms
The Prp19 U-box crystal structure suggests a common dimeric architecture for a class of oligomeric E3 ubiquitin ligases.
Vander Kooi CW, Ohi MD, Rosenberg JA, Oldham ML, Newcomer ME, Gould KL, Chazin WJ
(2006) Biochemistry 45: 121-30
MeSH Terms: Amino Acid Sequence, Binding Sites, Carrier Proteins, Crystallography, X-Ray, DNA Repair Enzymes, Dimerization, Humans, Models, Chemical, Molecular Sequence Data, Nuclear Proteins, Polyubiquitin, Protein Structure, Tertiary, RNA Splicing Factors, RNA, Small Nuclear, Substrate Specificity, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases
Show Abstract · Added December 10, 2013
Prp19 is an essential splicing factor and a member of the U-box family of E3 ubiquitin ligases. Prp19 forms a tetramer via a central coiled-coil domain. Here, we show the U-box domain of Prp19 exists as a dimer within the context of the Prp19 tetramer. A high-resolution structure of the homodimeric state of the Prp19 U-box was determined by X-ray crystallography. Mutation of the U-box dimer interface abrogates U-box dimer formation and is lethal in vivo. The structure of the U-box dimer enables construction of a complete model of Prp19 providing insights into how the tetrameric protein functions as an E3 ligase. Finally, comparison of the Prp19 U-box homodimer with the heterodimeric complex of BRCA1/BARD1 RING-finger domains uncovers a common architecture for a family of oligomeric U-box and RING-finger E3 ubiquitin ligases, which has mechanistic implications for E3 ligase-mediated polyubiquitination and E4 polyubiquitin ligases.
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4 Members
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17 MeSH Terms
Structural and functional analysis of essential pre-mRNA splicing factor Prp19p.
Ohi MD, Vander Kooi CW, Rosenberg JA, Ren L, Hirsch JP, Chazin WJ, Walz T, Gould KL
(2005) Mol Cell Biol 25: 451-60
MeSH Terms: Cell Cycle Proteins, Chromatography, Gel, Circular Dichroism, DNA Mutational Analysis, Dimerization, Genotype, Image Processing, Computer-Assisted, Immunoblotting, Immunoprecipitation, Microscopy, Electron, Models, Biological, Polymerase Chain Reaction, Protein Binding, Protein Conformation, Protein Structure, Tertiary, RNA Splicing, RNA Splicing Factors, RNA, Messenger, RNA-Binding Proteins, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Spliceosomes, Structure-Activity Relationship, Temperature, Two-Hybrid System Techniques, Ultracentrifugation
Show Abstract · Added December 10, 2013
U-box-containing Prp19p is an integral component of the Prp19p-associated complex (the nineteen complex, or NTC) that is essential for activation of the spliceosome. Prp19p makes numerous protein-protein contacts with other NTC components and is required for NTC stability. Here we show that Prp19p forms a tetramer in vitro and in vivo and we map the domain required for its oligomerization to a central tetrameric coiled-coil. Biochemical and in vivo analyses are consistent with Prp19p tetramerization providing an interaction surface for a single copy of its binding partner, Cef1p. Electron microscopy showed that the isolated Prp19p tetramer is an elongated particle consisting of four globular WD40 domains held together by a central stalk consisting of four N-terminal U-boxes and four coiled-coils. These structural and functional data provide a basis for understanding the role of Prp19p as a key architectural component of the NTC.
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4 Members
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29 MeSH Terms
Structural insights into the U-box, a domain associated with multi-ubiquitination.
Ohi MD, Vander Kooi CW, Rosenberg JA, Chazin WJ, Gould KL
(2003) Nat Struct Biol 10: 250-5
MeSH Terms: Amino Acid Sequence, Drug Stability, Hydrogen Bonding, Models, Molecular, Molecular Sequence Data, Molecular Structure, Mutation, Nuclear Magnetic Resonance, Biomolecular, Protein Structure, Tertiary, RNA Splicing, RNA Splicing Factors, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Spliceosomes, Ubiquitin
Show Abstract · Added December 10, 2013
The structure of the U-box in the essential Saccharomyces cerevisiae pre-mRNA splicing factor Prp19p has been determined by NMR. The conserved zinc-binding sites supporting the cross-brace arrangement in RING-finger domains are replaced by hydrogen-bonding networks in the U-box. These hydrogen-bonding networks are necessary for the structural stabilization and activity of the U-box. A conservative Val-->Ile point mutation in the Prp19p U-box domain leads to pre-mRNA splicing defects in vivo. NMR analysis of this mutant shows that the substitution disrupts structural integrity of the U-box domain. Furthermore, comparison of the Prp19p U-box domain with known RING-E2 complex structures demonstrates that both U-box and RING-fingers contain a conserved interaction surface. Mutagenesis of residues at this interface, while not perturbing the structure of the U-box, abrogates Prp19p function in vivo. These comparative structural and functional analyses imply that the U-box and its associated ubiquitin ligase activity are critical for Prp19p function in vivo.
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15 MeSH Terms