2024
Steering research on mRNA splicing in cancer towards clinical translation
Anczukow O, Allain F, Angarola B, Black D, Brooks A, Cheng C, Conesa A, Crosse E, Eyras E, Guccione E, Lu S, Neugebauer K, Sehgal P, Song X, Tothova Z, Valcárcel J, Weeks K, Yeo G, Thomas-Tikhonenko A. Steering research on mRNA splicing in cancer towards clinical translation. Nature Reviews Cancer 2024, 24: 887-905. PMID: 39384951, PMCID: PMC11698124, DOI: 10.1038/s41568-024-00750-2.Peer-Reviewed Original ResearchSplicing aberrationsMRNA splicingLong-read RNA sequencingRNA sequencingShort-read RNA sequencingCopy number variationsMis-spliced transcriptsRecurrent somatic mutationsSynthetic lethal approachSingle-cell levelSpliceosome componentsSplicing alterationsSplicing factorsCellular processesNumber variationsSpliceosome inhibitorsMRNA isoformsDNA repairSplicingSomatic mutationsTumor vulnerabilitiesLethal approachHuman cancersCancer initiationCancer progression
2023
Impaired Early Spliceosome Complex Assembly Underlies Gene Body Elongation Transcription Defect in SF3B1K700E
Boddu P, Gupta A, Roy R, De La Pena Avalos B, Herrero A, Zimmer J, Simon M, Chandhok N, King D, Neuenkirchen N, Dray E, Lin H, Kupfer G, Verma A, Neugebauer K, Pillai M. Impaired Early Spliceosome Complex Assembly Underlies Gene Body Elongation Transcription Defect in SF3B1K700E. Blood 2023, 142: 714. DOI: 10.1182/blood-2023-187303.Peer-Reviewed Original ResearchSplicing factorsChIP-seqK562 cell lineKey regulatory genesCell linesSingle mutant alleleNon-denaturing gelsAlternative splicingTranscriptional kineticsRegulatory genesSpliceosome assemblySplicing efficiencyMRNA splicingCRISPR/Progenitor populationsNeomorphic functionsMolecular mechanismsMutant allelesIsoform changesGene editingNovel mechanismMutationsSF mutationsRecurrent mutationsAssembly kinetics
2022
Zebrafish mutants in vegfab can affect endothelial cell proliferation without altering ERK phosphorylation and are phenocopied by loss of PI3K signaling
Lange M, Ohnesorge N, Hoffmann D, Rocha SF, Benedito R, Siekmann AF. Zebrafish mutants in vegfab can affect endothelial cell proliferation without altering ERK phosphorylation and are phenocopied by loss of PI3K signaling. Developmental Biology 2022, 486: 26-43. PMID: 35337795, PMCID: PMC11238767, DOI: 10.1016/j.ydbio.2022.03.006.Peer-Reviewed Original ResearchConceptsEndothelial cell migrationLong isoformPI3KCell migrationEC proliferationZebrafish trunkZebrafish mutantsMutant phenotypeCellular functionsIntersegmental blood vesselsMRNA splicingPI3-kinaseMAPK activationVegfabA PathwayERK phosphorylationExtracellular matrixEndothelial cell proliferationVEGFA isoformsIsoformsCell proliferationDistinct setsProliferationBlood vessel networkMutationsProteogenomic and clinical implications of unique recurrent splice variants in clear cell renal cell carcinoma.
Chang A, Stewart P, Chakiryan N, Soupir A, Tian Y, Du D, Teer J, Kim Y, Spiess P, Chahoud J, Zhang Y, Koomen J, Berglund A, Wang L, Robinson T, Manley B. Proteogenomic and clinical implications of unique recurrent splice variants in clear cell renal cell carcinoma. Journal Of Clinical Oncology 2022, 40: 380-380. DOI: 10.1200/jco.2022.40.6_suppl.380.Peer-Reviewed Original ResearchGenotype-Tissue Expression (GTEx) projectRNA-seq dataClear cell renal cell carcinomaSplice variantsClinical Proteomic Tumor Analysis ConsortiumBulk RNA-seq dataCell renal cell carcinomaAlternative mRNA splicingAberrant splice variantsCancer Cell Line EncyclopediaProteomic diversityProteogenomic analysisCancer Genome AtlasMRNA splicingExpression projectPathway enrichmentSplicing processTumor suppressorNew pathogenic mechanismGenomic mutationsNovel pipelineAnalysis ConsortiumOncogenic pathwaysCancer-specific survivalGenome Atlas
2021
Limited Proteolysis-Coupled Mass Spectrometry Identifies Phosphatidylinositol 4,5-Bisphosphate Effectors in Human Nuclear Proteome
Sztacho M, Šalovská B, Červenka J, Balaban C, Hoboth P, Hozák P. Limited Proteolysis-Coupled Mass Spectrometry Identifies Phosphatidylinositol 4,5-Bisphosphate Effectors in Human Nuclear Proteome. Cells 2021, 10: 68. PMID: 33406800, PMCID: PMC7824793, DOI: 10.3390/cells10010068.Peer-Reviewed Original ResearchConceptsGene expressionHuman nuclear proteomeLimited proteolysisLabel-free quantitative mass spectrometryNuclear pore complexGene ontology analysisCell cycle regulationQuantitative mass spectrometryNuclear proteomeProtein effectorsPore complexPol IIRNA splicingOntology analysisMRNA splicingCycle regulationPIP2 bindingProtein interactionsDNA repairBioinformatics analysisNuclear envelopeFunctional domainsMass spectrometry identifiesSpecific proteinsCell cycle
2019
Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis
Roczniak-Ferguson A, Ferguson SM. Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis. Life Science Alliance 2019, 2: e201900358. PMID: 31527135, PMCID: PMC6749094, DOI: 10.26508/lsa.201900358.Peer-Reviewed Original ResearchConceptsMultiple amyotrophic lateral sclerosisTDP-43 target genesNormal TDP-43 functionSpecific target transcriptsCell biological consequencesRNA-binding proteinTDP-43Disease-causing mutantsRegulation of cellPleiotropic requirementMultiple neurodegenerative diseasesOrganelle homeostasisTarget transcriptsMRNA splicingKnockout cellsTranscriptomic analysisMultiple organellesTDP-43 functionTarget genesCytoplasmic aggregatesNuclear envelopeTDP-43 mutationsTDP-43 depletionHuman TDP-43Morphological defects
2018
Altered Splicing from a Mutated Alternate Branch Point Is Common in Severe Alpha-Spectrin Linked Inherited Anemia
Lezon-Geyda K, Schulz V, Maksimova Y, Gallagher P. Altered Splicing from a Mutated Alternate Branch Point Is Common in Severe Alpha-Spectrin Linked Inherited Anemia. Blood 2018, 132: 503. DOI: 10.1182/blood-2018-99-117752.Peer-Reviewed Original ResearchMRNA transcriptsTermination codonK562 cellsMinigene assayIntron 30Precise genetic basisAcceptor sitesInsertion/deletion mutationsHereditary pyropoikilocytosisWhole-genome sequencingNMD inhibitorsAcceptor splice siteDiagnostic gene panelsGenome databaseMRNA splicingWild-type minigeneConsensus sitesAltered splicingExon 31Genetic basisTranscript productionErythroid cellsGene manipulationGenetic analysisWT backgroundThe Role of Maternal HP1a in Early Drosophila Embryogenesis via Regulation of Maternal Transcript Production
Park AR, Liu N, Neuenkirchen N, Guo Q, Lin H. The Role of Maternal HP1a in Early Drosophila Embryogenesis via Regulation of Maternal Transcript Production. Genetics 2018, 211: 201-217. PMID: 30442760, PMCID: PMC6325692, DOI: 10.1534/genetics.118.301704.Peer-Reviewed Original ResearchConceptsHeterochromatin protein 1aMaternal transcriptsEarly Drosophila embryogenesisGermline developmentDrosophila embryogenesisMRNA splicingCell divisionTranscript productionProtein 1AEpigenetic factorsDownregulates genesEmbryogenesisGenesTranscriptsSplicingOogenesisTranscriptionOrganogenesisRegulationRoleProductionNeurogenesisDivisionDevelopmentTranslationSRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells
Liang Y, Tebaldi T, Rejeski K, Joshi P, Stefani G, Taylor A, Song Y, Vasic R, Maziarz J, Balasubramanian K, Ardasheva A, Ding A, Quattrone A, Halene S. SRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells. Leukemia 2018, 32: 2659-2671. PMID: 29858584, PMCID: PMC6274620, DOI: 10.1038/s41375-018-0152-7.Peer-Reviewed Original ResearchConceptsSplicing factorsRNA processingAlternative splicingGene productsSplicing factor SRSF2Gene regulatory eventsAberrant alternative splicingSplice alterationsRecurrent mutationsSplicing proteinsHITS-CLIPSR familyMRNA splicingSplicing genesHematopoietic differentiationRegulatory eventsImpairs hematopoietic differentiationMolecular explanationWidespread modificationSplicingHematopoietic cellsMutationsBinding eventsOncogenesisProtein
2014
Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells
Wali VB, Haskins JW, Gilmore-Hebert M, Platt JT, Liu Z, Stern DF. Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells. Molecular Cancer Research 2014, 12: 1140-1155. PMID: 24829397, PMCID: PMC4728083, DOI: 10.1158/1541-7786.mcr-13-0637.Peer-Reviewed Original ResearchConceptsYAP/Hippo pathwayIsogenic MCF10A cellsMultiple structural isoformsAlternative mRNA splicingDivergent cellular responsesChIP-seq experimentsProteases/protease inhibitorsErbB4 isoformsMammary epithelial cellsAssociation of ErbB4Hippo pathwayMRNA splicingNovel molecular targetsTranscriptional profilingDivergent functionsTranscription factorsCYT-1Signaling activitiesMevalonate pathwayCellular responsesLuminal breast cancer cell linesDiverse biologic activitiesMCF10A cellsCYT-2Intracellular isoformsNuclear bodies: RNA‐rich powerhouses of the cell (471.3)
Neugebauer K, Machyna M, Straube K, Heyn P. Nuclear bodies: RNA‐rich powerhouses of the cell (471.3). The FASEB Journal 2014, 28 DOI: 10.1096/fasebj.28.1_supplement.471.3.Peer-Reviewed Original ResearchHistone locus bodyCajal bodiesNuclear bodiesZygotic genome activationTrafficking of RNAsEarly zebrafish embryogenesisSites of transcriptionSite of assemblyGenome activationSpliceosomal snRNPsZebrafish embryogenesisRNA processingHistone mRNAMRNA splicingEnd formationMacromolecular complexesLow-affinity interactionsNuclear morphologyCell nucleiCommon organizational featuresLipid bilayersRNAEfficient assemblyDifferent functionsMolecular composition
2012
Tri-snRNP-associated proteins interact with subunits of the TRAMP and nuclear exosome complexes, linking RNA decay and pre-mRNA splicing
Nag A, Steitz JA. Tri-snRNP-associated proteins interact with subunits of the TRAMP and nuclear exosome complexes, linking RNA decay and pre-mRNA splicing. RNA Biology 2012, 9: 334-342. PMID: 22336707, PMCID: PMC3384585, DOI: 10.4161/rna.19431.Peer-Reviewed Original ResearchConceptsDecay machineryMRNA splicingRNA decay machineryRNA decay factorsTri-snRNP complexNuclear exosome complexPM/SclYeast counterpartIntergenic transcriptsSnoRNA biogenesisExosome complexTri-snRNPRNA decayRRNA processingPhosphorylation sitesMRNA processingPutative componentsMtr4Prp31MachinerySplicingDifferent pathwaysProteinSpliceosomeBiogenesis
2010
Mechanisms of Pre-B Cell Receptor-Inactivation In Acute Lymphoblastic Leukemia
Duy C, Nowak D, Klemm L, Nahar R, Ng C, Elliott E, Hofmann W, Heisterkamp N, Lowell C, Koeffler P, Muschen M. Mechanisms of Pre-B Cell Receptor-Inactivation In Acute Lymphoblastic Leukemia. Blood 2010, 116: 147. DOI: 10.1182/blood.v116.21.147.147.Peer-Reviewed Original ResearchPre-B cell receptorImmunoglobulin μ chainCell receptor functionCell receptor stimulationTyrosine kinasePAX5 fusion genesSystematic gene expression analysisΜ chainsSplice variantsCell receptorRapid cell cycle arrestExon 16Immunoglobulin gene rearrangementsReceptor functionReceptor signal transductionPre-B cell receptor functionGene rearrangementsGene expression analysisLeukemia cellsDominant-negative waySyk tyrosine kinaseCell cycle arrestPre B cellsSH2 domainMRNA splicing
2008
Mutations affecting mRNA splicing are the most common molecular defect in patients with familial hemophagocytic lymphohistiocytosis type 3
Santoro A, Cannella S, Trizzino A, Bruno G, De Fusco C, Notarangelo L, Pende D, Griffiths G, Aricò M. Mutations affecting mRNA splicing are the most common molecular defect in patients with familial hemophagocytic lymphohistiocytosis type 3. Haematologica 2008, 93: 1086-1090. PMID: 18492689, DOI: 10.3324/haematol.12622.Peer-Reviewed Original ResearchConceptsDeep intronic mutationsIntronic mutationSplicing errorsFamilial hemophagocytic lymphohistiocytosisFamilial hemophagocytic lymphohistiocytosis type 3Hemophagocytic lymphohistiocytosisMRNA splicingRegulatory sequencesAberrant splicingImpaired splicingSplicing mutationSplicingAcceptor sitesExon 11Secretory granulesMunc13-4 proteinMolecular defectsMutationsFunctional impactUNC13D mutationsCellular cytotoxicityUNC13DClinical pictureLymphohistiocytosisMunc13
2006
Human Sec31B: a family of new mammalian orthologues of yeast Sec31p that associate with the COPII coat
Stankewich MC, Stabach PR, Morrow JS. Human Sec31B: a family of new mammalian orthologues of yeast Sec31p that associate with the COPII coat. Journal Of Cell Science 2006, 119: 958-969. PMID: 16495487, DOI: 10.1242/jcs.02751.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAmino Acid SequenceAnimalsCarrier ProteinsCell LineCells, CulturedChlorocebus aethiopsCloning, MolecularCOP-Coated VesiclesCOS CellsExonsGene Expression RegulationHumansMolecular Sequence DataPhosphoproteinsRNA, MessengerSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSequence AlignmentVesicular Transport ProteinsConceptsCOPII coatProline-rich C-terminal regionEndoplasmic reticulumTerminal proline-rich regionCOPII vesicle coatVesicular tubular clustersProline-rich regionWD repeat domainFull-length proteinAlternative mRNA splicingN-terminal domainC-terminal regionVesicle coatWD repeatsMammalian orthologuesVesicular trafficSecretory pathwayMRNA splicingExon utilizationExon 13Sec31pChromosome 10q24Gene productsSec31BSpecialized functions
1999
Brain and Muscle Express a Unique Alternative Transcript of αΙΙ Spectrin †
Cianci C, Zhang Z, Pradhan D, Morrow J. Brain and Muscle Express a Unique Alternative Transcript of αΙΙ Spectrin †. Biochemistry 1999, 38: 15721-15730. PMID: 10625438, DOI: 10.1021/bi991458k.Peer-Reviewed Original ResearchConceptsAlternative mRNA splicingMRNA splicingAlphaII-spectrinBp insertionNovel protein interaction siteEmbryonic tissuesInsert 2Alternative exon usageProtein interaction sitesAmino acid sequenceDifferent splice formsAmino acid insertionMouse embryonic tissuesInsert-1Amino acid substitutionsSkeletal muscleGene familyDynamic molecular modelingMature proteinUnanticipated functionAlternative splicingExon usageIndividual transcriptsAlternative transcriptsSplice forms
1997
Inhibition of mammalian spliceosome assembly and pre-mRNA splicing by peptide inhibitors of protein kinases.
Parker AR, Steitz JA. Inhibition of mammalian spliceosome assembly and pre-mRNA splicing by peptide inhibitors of protein kinases. RNA 1997, 3: 1301-12. PMID: 9409621, PMCID: PMC1369569.Peer-Reviewed Original ResearchConceptsCalmodulin binding domainMammalian spliceosome assemblySpliceosome assemblyMRNA splicingSplicing activityCaMK IIGS peptideProtein kinase CAutophosphorylation eventsCalmodulin kinase IIProlonged incubationProtein kinaseSplicing reactionSplicing assaysBinding domainsKinase IISplicingKinase CPeptide inhibitorDistinct mechanismsProteinKinaseCompetitive inhibitorAssemblyDistinct eventsDistribution of pre-mRNA splicing factors at sites of RNA polymerase II transcription.
Neugebauer K, Roth M. Distribution of pre-mRNA splicing factors at sites of RNA polymerase II transcription. Genes & Development 1997, 11: 1148-1159. PMID: 9159396, DOI: 10.1101/gad.11.9.1148.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalBinding SitesCell NucleusFluorescent Antibody Technique, IndirectHeLa CellsHumansNuclear ProteinsPhosphoproteinsRibonucleoproteins, Small NuclearRNA Polymerase IIRNA PrecursorsRNA SplicingRNA-Binding ProteinsSerine-Arginine Splicing FactorsTranscription, GeneticUridine TriphosphateConceptsRNA polymerase II transcriptionPolymerase II transcriptionMRNA splicing factorsSplicing factorsSR familyPre-mRNA splicingVisualization of hundredsHeLa cell nucleiSplicing regulatorsActive genesTranscription unitMRNA splicingGene regulatorsGene transcriptionPre-mRNADistinct functionsRNA synthesisTranscriptionCell nucleiSplicingSingle memberRegulatorActive site
1996
More Sm snRNAs from Vertebrate Cells
Yu Y, Tarn W, Yario T, Steitz J. More Sm snRNAs from Vertebrate Cells. Experimental Cell Research 1996, 229: 276-281. PMID: 8986610, DOI: 10.1006/excr.1996.0372.Peer-Reviewed Original Research
1993
Mutations in the conserved loop of human U5 snRNA generate use of novel cryptic 5′ splice sites in vivo.
Cortes JJ, Sontheimer EJ, Seiwert SD, Steitz JA. Mutations in the conserved loop of human U5 snRNA generate use of novel cryptic 5′ splice sites in vivo. The EMBO Journal 1993, 12: 5181-5189. PMID: 8262061, PMCID: PMC413781, DOI: 10.1002/j.1460-2075.1993.tb06213.x.Peer-Reviewed Original ResearchConceptsSplice siteRabbit beta-globin geneBeta-globin transcriptsBeta-globin geneU5 genesConserved loopMRNA splicingU5 snRNASecond intronFirst exonExon sequencesLoop mutantsSecond exonExpression vectorTransient transfectionCryptic sitesNovel siteHeLa cellsGT dinucleotideExonsExon 1U5 sequencesSnRNAMutationsVivo system
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