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, 1-19. PMID: 39384951, 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 progressionEmerging and re-emerging themes in co-transcriptional pre-mRNA splicing
Carrocci T, Neugebauer K. Emerging and re-emerging themes in co-transcriptional pre-mRNA splicing. Molecular Cell 2024, 84: 3656-3666. PMID: 39366353, PMCID: PMC11463726, DOI: 10.1016/j.molcel.2024.08.036.Peer-Reviewed Original ResearchConceptsPre-mRNA splicingCo-transcriptional pre-mRNA splicingCo-transcriptional RNA foldingCo-transcriptional processesRNA polymerase IIPre-messenger RNAFunctional messenger RNAsCapping enzymePolymerase IIDelayed splicingPolyadenylation machinerySplicing eventsPre-mRNAGene regulationMacromolecular machinesRNA foldingRNA synthesisMRNA isoformsProtein productionGene expressionSplicingRNARegulatory importanceCross-regulationMessenger RNAPhosphorylation of the nuclear poly(A) binding protein (PABPN1) during mitosis protects mRNA from hyperadenylation and maintains transcriptome dynamics
Gordon J, Phizicky D, Schärfen L, Brown C, Escayola D, Kanyo J, Lam T, Simon M, Neugebauer K. Phosphorylation of the nuclear poly(A) binding protein (PABPN1) during mitosis protects mRNA from hyperadenylation and maintains transcriptome dynamics. Nucleic Acids Research 2024, 52: 9886-9903. PMID: 38943343, PMCID: PMC11381358, DOI: 10.1093/nar/gkae562.Peer-Reviewed Original ResearchPoly(A)-binding proteinTranscriptome dynamicsNuclear poly(A) binding proteinPoly(A) binding proteinMode of gene regulationFunctional consequences of phosphorylationLong-read sequencingIncreased mRNA turnoverNucleo-cytoplasmic exportConsequences of phosphorylationRegulation of poly(ACohort of mRNAsGene expression programsMRNA biogenesisCytoplasmic mixingMRNA turnoverGene regulationShorter poly(ARNA stabilityMitotic kinasesPoly(ACell cycleMRNA synthesisIncreased transcriptionBinding proteinMultiple roles for AU-rich RNA binding proteins in the development of haematologic malignancies and their resistance to chemotherapy
Podszywalow-Bartnicka P, Neugebauer K. Multiple roles for AU-rich RNA binding proteins in the development of haematologic malignancies and their resistance to chemotherapy. RNA Biology 2024, 21: 1-17. PMID: 38798162, PMCID: PMC11135835, DOI: 10.1080/15476286.2024.2346688.Peer-Reviewed Original ResearchConceptsARE-binding proteinsRNA-binding proteinsAU-rich elementsStress granulesBinding proteinTranslational regulation of mRNAsImpact alternative splicingCytoplasmic stress granulesProtein-RNA bindingAdaptation to microenvironmentProtein-RNA networksBinding to AU-rich elementsCancer cell proteomePost-transcriptional regulationAU-rich RNA-binding proteinsRegulation of mRNAsChemotherapy resistanceGene expression levelsSequence motifsProtein-RNAMRNA structureMature mRNATranslational regulationAlternative splicingCell proteomeTranscription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape
Boddu P, Gupta A, Roy R, De La Peña Avalos B, Olazabal-Herrero A, Neuenkirchen N, Zimmer J, Chandhok N, King D, Nannya Y, Ogawa S, Lin H, Simon M, Dray E, Kupfer G, Verma A, Neugebauer K, Pillai M. Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape. Molecular Cell 2024, 84: 1475-1495.e18. PMID: 38521065, PMCID: PMC11061666, DOI: 10.1016/j.molcel.2024.02.032.Peer-Reviewed Original ResearchRate of RNA polymerase IIChromatin landscapeElongation defectsElongation rate of RNA polymerase IIImpaired protein-protein interactionsSplicing of pre-messenger RNATranscription elongation defectsRNA polymerase IIProtein-protein interactionsPre-messenger RNACancer-associated mutationsIsogenic cell linesSin3/HDAC complexGene bodiesPolymerase IIChromatin accessibilityH3K4me3 markChromatin changesMutant SF3B1ChromatinMutant mouse modelsEpigenetic disordersEpigenetic factorsHuman diseasesMutant stateCo-transcriptional gene regulation in eukaryotes and prokaryotes
Shine M, Gordon J, Schärfen L, Zigackova D, Herzel L, Neugebauer K. Co-transcriptional gene regulation in eukaryotes and prokaryotes. Nature Reviews Molecular Cell Biology 2024, 25: 534-554. PMID: 38509203, PMCID: PMC11199108, DOI: 10.1038/s41580-024-00706-2.Peer-Reviewed Original ResearchRNA polymeraseRNA biogenesisRNA processingGene regulationDevelopment of RNA sequencingTranscription to translationRNA processing intermediatesGene expression stepsCo-transcriptional activityCellular stress responseNascent RNATranscriptional readthroughNascent transcriptsTranscriptional coordinationIntron retentionRNA foldingEukaryotesProkaryotesExpression stepsRNA sequencingTransient transcriptionGene expressionTranscriptionStress responseRNAA correlative quantitative phase contrast and fluorescence super-resolution microscope for imaging molecules in their cellular context
Bao Y, Marin Z, Zhang C, Neugebauer K, Baddeley D, Shribak M, Bewersdorf J. A correlative quantitative phase contrast and fluorescence super-resolution microscope for imaging molecules in their cellular context. Biophysical Journal 2024, 123: 290a. DOI: 10.1016/j.bpj.2023.11.1808.Peer-Reviewed Original ResearchHow cell biology can save the planet
Neugebauer K. How cell biology can save the planet. Nature Cell Biology 2024, 26: 4-4. PMID: 38228830, DOI: 10.1038/s41556-023-01305-7.Peer-Reviewed Original Research
2023
Five questions on how biochemistry can combat climate change
Chen K, Guo Y, How K, Acosta A, Documet D, Liang C, Arul D, Wood S, Moon K, Oliver L, Fajardo E, Kopyto M, Shine M, Neugebauer K. Five questions on how biochemistry can combat climate change. BBA Advances 2023, 4: 100111. PMID: 38075469, PMCID: PMC10709155, DOI: 10.1016/j.bbadva.2023.100111.Peer-Reviewed Original ResearchClimate changeCell biologyGreater ecosystemMolecular biophysicsEnvironmental changesEnvironmental conditionsOrganismsBiochemistryMolecular pointNew diseaseHuman activitiesDispersalMicrobesGeneticsBiologyEcosystemsPlantsGlobal warmingPathwayHigh levelsSalt concentrationBiophysicsCellsAccumulationWeather patternsSplicing under stress: A matter of time and place
Podszywalow-Bartnicka P, Neugebauer K. Splicing under stress: A matter of time and place. Journal Of Cell Biology 2023, 222: e202311014. PMID: 37988026, PMCID: PMC10660129, DOI: 10.1083/jcb.202311014.Peer-Reviewed Original ResearchImpaired 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 kineticsTranscription Defects in SF3B1K700E Induce Targetable Alterations in the Chromatin Landscape
Boddu P, Gupta A, Roy R, Herrero A, Verma A, Neugebauer K, Pillai M. Transcription Defects in SF3B1K700E Induce Targetable Alterations in the Chromatin Landscape. Blood 2023, 142: 709. DOI: 10.1182/blood-2023-188083.Peer-Reviewed Original ResearchChromatin organizationSuch epigenetic changesGenome editing approachesRNA splicing factorsChromatin landscapeSingle mutant alleleEpigenetic landscapeGenomic integrityTranscription defectTranscription kineticsSplicing factorsChIP-seqEpigenetic regulatorsEpigenetic changesEpigenetic therapyMutant allelesEditing approachesFactor mutationsK562 cell lineDownstream effectsCell linesMyeloid disordersClonal myeloid disordersHDAC pathwayMutationsThe promoter as a trip navigator: Guiding alternative polyadenylation site destinations
Bergfort A, Neugebauer K. The promoter as a trip navigator: Guiding alternative polyadenylation site destinations. Molecular Cell 2023, 83: 2395-2397. PMID: 37478824, DOI: 10.1016/j.molcel.2023.06.022.Commentaries, Editorials and LettersTudor–dimethylarginine interactions: the condensed version
Šimčíková D, Gelles-Watnick S, Neugebauer K. Tudor–dimethylarginine interactions: the condensed version. Trends In Biochemical Sciences 2023, 48: 689-698. PMID: 37156649, PMCID: PMC10524826, DOI: 10.1016/j.tibs.2023.04.003.Peer-Reviewed Original ResearchConceptsSurvival motor neuron (SMN) proteinTudor domainDiverse cellular functionsRNA-RNA interactionsSMN Tudor domainMotor neuron proteinCellular functionsProtein localizationProtein-RNASpinal muscular atrophyProtein ligandsNeuron proteinIntramolecular interactionsMuscular atrophyProteinInteractionFunctionLigandsModificationBiomolecularCellsLocalizationOpen questionDomainFormationAn integrated platform for high-throughput nanoscopy
Barentine A, Lin Y, Courvan E, Kidd P, Liu M, Balduf L, Phan T, Rivera-Molina F, Grace M, Marin Z, Lessard M, Rios Chen J, Wang S, Neugebauer K, Bewersdorf J, Baddeley D. An integrated platform for high-throughput nanoscopy. Nature Biotechnology 2023, 41: 1549-1556. PMID: 36914886, PMCID: PMC10497732, DOI: 10.1038/s41587-023-01702-1.Peer-Reviewed Original ResearchConceptsLarge data volumesUser-defined extensionsPlugin frameworkData compressionData volumeCamera frameFrame rateAnalysis platformAcquisition taskPlatformIntegrated acquisitionThroughputSingle-molecule localization microscopyTypical throughputHundreds of cellsThree-dimensional fluorescenceFrameworkTens of cellsLocalization microscopyWorkflow
2022
Transcriptome-wide mapping reveals a diverse dihydrouridine landscape including mRNA
Draycott AS, Schaening-Burgos C, Rojas-Duran MF, Wilson L, Schärfen L, Neugebauer KM, Nachtergaele S, Gilbert WV. Transcriptome-wide mapping reveals a diverse dihydrouridine landscape including mRNA. PLOS Biology 2022, 20: e3001622. PMID: 35609439, PMCID: PMC9129914, DOI: 10.1371/journal.pbio.3001622.Peer-Reviewed Original ResearchConceptsTranscriptome-wide mappingSmall nucleolar RNAsFunctional RNA structuresSingle-nucleotide resolutionStem-loop regionEukaryotic ribosomesNucleolar RNAsPre-mRNARNA structureRNA targetsDihydrouridine synthaseHuman diseasesMRNARNANovel classFunctional componentsSplicingTRNARibosomesYeastDependent changesLandscapeOrganismsDihydrouridineSequencingIntegrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)
Karmakar S, Ramirez O, Paul KV, Gupta AK, Kumari V, Botti V, de los Mozos IR, Neuenkirchen N, Ross RJ, Karanicolas J, Neugebauer KM, Pillai MM. Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2). NAR Cancer 2022, 4: zcac015. PMID: 35528200, PMCID: PMC9070473, DOI: 10.1093/narcan/zcac015.Peer-Reviewed Original ResearchRNA binding proteinMusashi-2Functional targetIntegrative genome-wide analysisGenome-wide analysisIndividual-nucleotide resolutionAsymmetric cell divisionCell fate decisionsThousands of mRNAsKey downstream regulatorProtein Musashi-2Polysome profilingFate decisionsEukaryotic translation initiation factor 3aNucleotide resolutionCell divisionDirect RNATranslational inductionCancer stem cellsDownstream regulatorsUntranslated regionIndirect targetsBinding proteinDirect targetMere bindingPrecision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies
Biancon G, Joshi P, Zimmer JT, Hunck T, Gao Y, Lessard MD, Courchaine E, Barentine AES, Machyna M, Botti V, Qin A, Gbyli R, Patel A, Song Y, Kiefer L, Viero G, Neuenkirchen N, Lin H, Bewersdorf J, Simon MD, Neugebauer KM, Tebaldi T, Halene S. Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Molecular Cell 2022, 82: 1107-1122.e7. PMID: 35303483, PMCID: PMC8988922, DOI: 10.1016/j.molcel.2022.02.025.Peer-Reviewed Original ResearchPYME: an integrated platform for high-throughput nanoscopy
Barentine A, Lin Y, Courvan E, Kidd P, Liu M, Balduf L, Phan T, Rivera-Molina F, Grace M, Marin Z, Chen J, Wang S, Neugebauer K, Baddeley D, Bewersdorf J. PYME: an integrated platform for high-throughput nanoscopy. Biophysical Journal 2022, 121: 137a. DOI: 10.1016/j.bpj.2021.11.2009.Peer-Reviewed Original ResearchIdentification of Alternative Polyadenylation in Cyanidioschyzon merolae Through Long-Read Sequencing of mRNA
Schärfen L, Zigackova D, Reimer KA, Stark MR, Slat VA, Francoeur NJ, Wells ML, Zhou L, Blackshear PJ, Neugebauer KM, Rader SD. Identification of Alternative Polyadenylation in Cyanidioschyzon merolae Through Long-Read Sequencing of mRNA. Frontiers In Genetics 2022, 12: 818697. PMID: 35154260, PMCID: PMC8831791, DOI: 10.3389/fgene.2021.818697.Peer-Reviewed Original ResearchAlternative polyadenylationNon-model organismsRNA processing pathwaysLong-Read SequencingCyanidioschyzon merolaeSplicing statusSplicing machineryMammalian cellsRegulatory stepMRNA stabilityRed algaVolcanic hot springsGene expressionRich mediumPolyadenylationBiological importanceOrganismsSite usageProtein expressionHot springsYeastAlgaProcessing pathwaysSequencingMRNA