2019
Intra-Vκ Cluster Recombination Shapes the Ig Kappa Locus Repertoire
Shinoda K, Maman Y, Canela A, Schatz DG, Livak F, Nussenzweig A. Intra-Vκ Cluster Recombination Shapes the Ig Kappa Locus Repertoire. Cell Reports 2019, 29: 4471-4481.e6. PMID: 31875554, PMCID: PMC8214342, DOI: 10.1016/j.celrep.2019.11.088.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksRecombination signal sequencesVκ gene segmentsGene segmentsDouble-strand breaksVariable gene segmentsRAG proteinsSignal sequenceV-J rearrangementRecombination eventsSpacer regionVκ-JκRecombinationLevels of breakageComplete absenceProteinLarge fractionDeletionJκSequence
2017
Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks
Fisher MR, Rivera-Reyes A, Bloch NB, Schatz DG, Bassing CH. Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks. The Journal Of Immunology 2017, 198: 2943-2956. PMID: 28213501, PMCID: PMC5360515, DOI: 10.4049/jimmunol.1601639.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksDNA damage responseRAG1/RAG2Double-strand breaksRAG DNA double-strand breaksMultiple genomic locationsTranscription of genesNF-κB transcription factorsDSB responseGenomic integrityGenomic locationATM kinaseTranscriptional repressionRAG cleavageCellular functionsDamage responseLocus recombinationMammalian cellsRAG1 proteinTranscription factorsModulator proteinRAG expressionAtaxia telangiectasiaTranscriptional inhibitionDevelopmental stages
2015
Mapping and Quantitation of the Interaction between the Recombination Activating Gene Proteins RAG1 and RAG2* ♦
Zhang YH, Shetty K, Surleac MD, Petrescu AJ, Schatz DG. Mapping and Quantitation of the Interaction between the Recombination Activating Gene Proteins RAG1 and RAG2* ♦. Journal Of Biological Chemistry 2015, 290: 11802-11817. PMID: 25745109, PMCID: PMC4424321, DOI: 10.1074/jbc.m115.638627.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCatalytic DomainDNA-Binding ProteinsGene Expression RegulationGenome, HumanHEK293 CellsHomeodomain ProteinsHumansInterferometryMaleMiceMice, Inbred C57BLMolecular Sequence DataMutationNuclear ProteinsProtein BindingProtein Interaction MappingProtein Structure, SecondaryThymus GlandV(D)J RecombinationVDJ RecombinasesConceptsRegion of RAG1Α-helixZinc finger regionResidues N-terminalActive siteAcidic amino acidsPulldown assaysAccessory factorsHermes transposaseProteins RAG1Finger regionRAG activityQuantitative Western blottingC-terminusRAG endonucleaseN-terminalCatalytic functionRAG1Amino acidsDNA cleavageRAG2Nuclear concentrationRecombination activityCatalytic centerBiolayer interferometry
2014
The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells
Karo JM, Schatz DG, Sun JC. The RAG Recombinase Dictates Functional Heterogeneity and Cellular Fitness in Natural Killer Cells. Cell 2014, 159: 94-107. PMID: 25259923, PMCID: PMC4371485, DOI: 10.1016/j.cell.2014.08.026.Peer-Reviewed Original ResearchConceptsRecombination-activating geneDNA damage response mediatorsInnate lymphoid cellsNatural killer cellsAntigen receptor genesCellular fitnessJawed vertebratesRAG recombinaseCellular stressInnate lymphocytesNovel functionDNA breaksKiller cellsEndonuclease activityUnexpected roleCleavage eventsAdaptive immune cellsReceptor geneReduced expressionGenesFunctional heterogeneityCellsImmune cellsResponse mediatorsFitness
2013
Higher-Order Looping and Nuclear Organization of Tcra Facilitate Targeted RAG Cleavage and Regulated Rearrangement in Recombination Centers
Chaumeil J, Micsinai M, Ntziachristos P, Deriano L, Wang J, Ji Y, Nora EP, Rodesch MJ, Jeddeloh JA, Aifantis I, Kluger Y, Schatz DG, Skok JA. Higher-Order Looping and Nuclear Organization of Tcra Facilitate Targeted RAG Cleavage and Regulated Rearrangement in Recombination Centers. Cell Reports 2013, 3: 359-370. PMID: 23416051, PMCID: PMC3664546, DOI: 10.1016/j.celrep.2013.01.024.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsCell NucleusDNA DamageDNA-Binding ProteinsGenetic LociGenomic InstabilityHistonesHomeodomain ProteinsMiceMice, Inbred C57BLMice, Inbred CBAMice, KnockoutProtein Serine-Threonine KinasesReceptors, Antigen, T-Cell, alpha-betaTumor Suppressor ProteinsV(D)J RecombinationConceptsAntigen receptor lociRegulated rearrangementsGenome stabilityNuclear organizationRAG cleavageRAG recombinaseNuclear accessibilityRAG bindingCellular transformationΑ locusRecombination eventsReceptor locusDiverse arrayCell receptorLociLoop formationTight controlRegulationCleavageFocal bindingGenetic anomaliesBindingKey determinantRearrangementTranscription
2010
Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions
Maul RW, Saribasak H, Martomo SA, McClure RL, Yang W, Vaisman A, Gramlich HS, Schatz DG, Woodgate R, Wilson DM, Gearhart PJ. Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions. Nature Immunology 2010, 12: 70-76. PMID: 21151102, PMCID: PMC3653439, DOI: 10.1038/ni.1970.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigenic VariationB-LymphocytesCells, CulturedCytidine DeaminaseDNA-(Apurinic or Apyrimidinic Site) LyaseImmunoglobulin Class SwitchingImmunoglobulin Variable RegionInterleukin-4LipopolysaccharidesLymphocyte ActivationMiceMice, Inbred C57BLMice, KnockoutModels, ChemicalSpleenUracilUracil-DNA GlycosidasePromoters, enhancers, and transcription target RAG1 binding during V(D)J recombination
Ji Y, Little AJ, Banerjee JK, Hao B, Oltz EM, Krangel MS, Schatz DG. Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination. Journal Of Experimental Medicine 2010, 207: 2809-2816. PMID: 21115692, PMCID: PMC3005232, DOI: 10.1084/jem.20101136.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAnimalsBinding, CompetitiveChromatin ImmunoprecipitationDNAEnhancer Elements, GeneticFemaleGene RearrangementGenes, ImmunoglobulinGenotypeHistonesHMGB1 ProteinHomeodomain ProteinsMaleMiceMice, Inbred C57BLMice, KnockoutPromoter Regions, GeneticProtein BindingReceptors, Antigen, T-Cell, alpha-betaRecombination, GeneticTranscription, GeneticVDJ RecombinasesThe In Vivo Pattern of Binding of RAG1 and RAG2 to Antigen Receptor Loci
Ji Y, Resch W, Corbett E, Yamane A, Casellas R, Schatz DG. The In Vivo Pattern of Binding of RAG1 and RAG2 to Antigen Receptor Loci. Cell 2010, 141: 419-431. PMID: 20398922, PMCID: PMC2879619, DOI: 10.1016/j.cell.2010.03.010.Peer-Reviewed Original ResearchConceptsJ gene segmentsRAG proteinsGene segmentsSignal sequenceLineage-specific mannerAntigen receptor lociRecombination signal sequencesLysine 4Active chromatinRAG2 bindThousands of sitesHistone 3Receptor locusDevelopmental stagesD gene segmentsDiscrete sitesCritical initial stepVivo patternRAG1BindingRAG2Beta JProteinRecombinationSpecific binding
2009
RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci
Hewitt SL, Yin B, Ji Y, Chaumeil J, Marszalek K, Tenthorey J, Salvagiotto G, Steinel N, Ramsey LB, Ghysdael J, Farrar MA, Sleckman BP, Schatz DG, Busslinger M, Bassing CH, Skok JA. RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci. Nature Immunology 2009, 10: 655-664. PMID: 19448632, PMCID: PMC2693356, DOI: 10.1038/ni.1735.Peer-Reviewed Original ResearchAllelesAnimalsAtaxia Telangiectasia Mutated ProteinsB-LymphocytesCell Cycle ProteinsCells, CulturedDNA BreaksDNA-Binding ProteinsGene RearrangementHomeodomain ProteinsImmunoglobulinsMiceMice, Inbred C57BLMice, KnockoutProtein Serine-Threonine KinasesRecombination, GeneticTumor Suppressor ProteinsVDJ Recombinases
2006
Origins of peripheral B cells in IL-7 receptor-deficient mice
Hesslein DG, Yang SY, Schatz DG. Origins of peripheral B cells in IL-7 receptor-deficient mice. Molecular Immunology 2006, 43: 326-334. PMID: 16310046, DOI: 10.1016/j.molimm.2005.02.010.Peer-Reviewed Original ResearchConceptsIL-7Ralpha-deficient miceB cell populationsB cellsBone marrowSplenic B cellsIL-7RalphaCell percentageIL-7 receptor-deficient miceCell populationsReceptor-deficient micePeripheral B cellsSplenic B cell populationSpleens of adultBone marrow-derived B cellsReceptor alpha geneEarly lymphoid differentiationAdult bone marrowSplenic populationsPeripheral BNeonatal developmentB cell developmentFollicular cellsMarrowMiceFetal liver
2004
Pax5-Deficient Mice Exhibit Early Onset Osteopenia with Increased Osteoclast Progenitors
Horowitz MC, Xi Y, Pflugh DL, Hesslein DG, Schatz DG, Lorenzo JA, Bothwell AL. Pax5-Deficient Mice Exhibit Early Onset Osteopenia with Increased Osteoclast Progenitors. The Journal Of Immunology 2004, 173: 6583-6591. PMID: 15557148, DOI: 10.4049/jimmunol.173.11.6583.Peer-Reviewed Original ResearchConceptsNumber of osteoclastsSpleen cellsB cellsOsteoclast developmentB cell-deficient miceCell-deficient miceControl spleen cellsB lymphocyte lineage cellsBone marrow cellsB-cell lineagePro-B cell stageMonocyte phenotypeBone massOsteoclast precursorsMice exhibitOsteoclast progenitorsMarrow cellsGrowth factorMiceOsteoclastsLineage cellsOsteopeniaCell lineagesCellsAdherent cellsStaggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to Sµ in Ig class switch recombination
Rush JS, Fugmann SD, Schatz DG. Staggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to Sµ in Ig class switch recombination. International Immunology 2004, 16: 549-557. PMID: 15039385, DOI: 10.1093/intimm/dxh057.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalBlotting, SouthernB-LymphocytesCell DivisionCytidine DeaminaseDeoxyribonucleases, Type II Site-SpecificDNADNA DamageDNA PrimersFlow CytometryGene ExpressionImmunoglobulin Class SwitchingImmunoglobulin DImmunoglobulin GImmunoglobulin Switch RegionInterleukin-4LipopolysaccharidesMiceMice, Inbred C57BLMice, KnockoutPlasmidsPolymerase Chain ReactionRecombination, GeneticConceptsClass switch recombinationDNA double-strand breaksPredominant DNA lesionsDouble-strand breaksActivation-induced cytidine deaminaseDNA lesionsSwitch recombinationAID-dependent DNA double-strand breaksStrand breaksIg class switch recombinationLigation-mediated PCRS mu regionCellular regulationKinetics of inductionMolecular detailsMurine B cellsDNA DSBsStaggered breaksCytidine deaminaseDSBsMu regionMinor speciesB cellsS muEffector propertiesPartial reconstitution of V(D)J rearrangement and lymphocyte development in RAG-deficient mice expressing inducible, tetracycline-regulated RAG transgenes
Shockett PE, Zhou S, Hong X, Schatz DG. Partial reconstitution of V(D)J rearrangement and lymphocyte development in RAG-deficient mice expressing inducible, tetracycline-regulated RAG transgenes. Molecular Immunology 2004, 40: 813-829. PMID: 14687938, DOI: 10.1016/j.molimm.2003.09.009.Peer-Reviewed Original ResearchConceptsPeripheral lymphoid organsIGK locusInducible gene expressionLymph nodesCell reconstitutionLymphoid organsTransgenic miceTRB locusTRD locusT-cell reconstitutionB-cell reconstitutionMammalian cellsRAG-deficient miceSignal endsTra locusRecombination signalsInducible activationGene expressionTCR beta chainFunctional expressionLymphocyte developmentLociRAG2 mRNALymphocyte reconstitutionTransgeneUp-Regulation of Hlx in Immature Th Cells Induces IFN-γ Expression
Zheng WP, Zhao Q, Zhao X, Li B, Hubank M, Schatz DG, Flavell RA. Up-Regulation of Hlx in Immature Th Cells Induces IFN-γ Expression. The Journal Of Immunology 2004, 172: 114-122. PMID: 14688316, DOI: 10.4049/jimmunol.172.1.114.Peer-Reviewed Original ResearchMeSH KeywordsAdjuvants, ImmunologicAdoptive TransferAnimalsCD4-Positive T-LymphocytesCell DifferentiationCells, CulturedHemocyaninsHomeodomain ProteinsInjections, IntravenousInjections, SubcutaneousInterferon-gammaInterphaseMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicTh1 CellsT-Lymphocytes, Helper-InducerTranscription FactorsUp-RegulationConceptsCD4 T cellsTransgenic CD4 T cellsTh2-polarizing conditionsTh1 cell differentiationTh cellsT cellsTh1 cellsIFN-gammaKeyhole limpet hemocyanin immunizationNormal CD4 T cellsTime pointsIntracellular cytokine stainingIFN-γ expressionIFN-gamma expressionEarly time pointsCytokine stainingTh2 cellsNaive precursorsCell differentiationSpecific time pointsThymocyte populationTransgenic miceMarked reductionAberrant expressionRetroviral infection
2003
Pax5 is required for recombination of transcribed, acetylated, 5′ IgH V gene segments
Hesslein DG, Pflugh DL, Chowdhury D, Bothwell AL, Sen R, Schatz DG. Pax5 is required for recombination of transcribed, acetylated, 5′ IgH V gene segments. Genes & Development 2003, 17: 37-42. PMID: 12514097, PMCID: PMC195966, DOI: 10.1101/gad.1031403.Peer-Reviewed Original ResearchAcetylationAllelesAnimalsB-LymphocytesChromatinDNA NucleotidyltransferasesDNA-Binding ProteinsGene Rearrangement, B-Lymphocyte, Heavy ChainGenes, ImmunoglobulinGenes, RAG-1HistonesHomeodomain ProteinsImmunoglobulin Heavy ChainsImmunoglobulin Variable RegionMiceMice, Inbred C57BLMice, KnockoutPAX5 Transcription FactorTranscription FactorsTranscription, GeneticVDJ Recombinases
2000
Cell-cycle-regulated DNA double-strand breaks in somatic hypermutation of immunoglobulin genes
Papavasiliou F, Schatz D. Cell-cycle-regulated DNA double-strand breaks in somatic hypermutation of immunoglobulin genes. Nature 2000, 408: 216-221. PMID: 11089977, DOI: 10.1038/35041599.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksDouble-strand breaksSomatic hypermutationRepair of DSBsVariable region promotersImmunoglobulin variable region genesDNA replicationHomologous recombinationHeterologous promoterSpecific residuesVariable genesNearby mutationsRegion promoterVariable region genesImmunoglobulin genesHeterologous sequencesChromosomal translocationsPoint mutationsGenesRegion genesMutationsHypermutationTranscriptionPromoterB-cell tumorsGenetic Modulation of T Cell Receptor Gene Segment Usage during Somatic Recombination
Livak F, Burtrum D, Rowen L, Schatz D, Petrie H. Genetic Modulation of T Cell Receptor Gene Segment Usage during Somatic Recombination. Journal Of Experimental Medicine 2000, 192: 1191-1196. PMID: 11034609, PMCID: PMC2195867, DOI: 10.1084/jem.192.8.1191.Peer-Reviewed Original ResearchConceptsRecombination signal sequencesFlanking recombination signal sequencesGene segment usageUseful gene productsLymphocyte antigen receptorsSegment usageSignal sequenceSomatic cellsCombinatorial joiningGene productsSomatic recombinationRecombinase activityGenetic modulationGene segmentsBeta gene segment usageMature T lymphocytesD betaSynaptic complexGermline genesTotal repertoireNaive repertoireAntigen receptorRecombinationRepertoireBiased representation
1999
Characterization of TCR gene rearrangements during adult murine T cell development.
Livák F, Tourigny M, Schatz D, Petrie H. Characterization of TCR gene rearrangements during adult murine T cell development. The Journal Of Immunology 1999, 162: 2575-80. PMID: 10072498, DOI: 10.4049/jimmunol.162.5.2575.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGene Rearrangement, beta-Chain T-Cell Antigen ReceptorGene Rearrangement, delta-Chain T-Cell Antigen ReceptorGene Rearrangement, gamma-Chain T-Cell Antigen ReceptorGene Rearrangement, T-LymphocyteHyaluronan ReceptorsMiceMice, Inbred C57BLPolymerase Chain ReactionReceptors, Interleukin-2T-LymphocytesConceptsTCRbeta locusTCRdelta locusGammadelta T cell lineagesMurine T cell developmentTCR gene rearrangementsT lineage cellsGene rearrangementsT cell developmentLineage decisionsLocus recombinationLineage commitmentProductive rearrangementsIrreversible commitmentCell lineagesDelta geneMolecular evidenceCell developmentTCRbeta rearrangementsDevelopmental stagesT-cell lineageTCR complexLociLineage cellsLineagesGenesDistinct effects of Jak3 signaling on alphabeta and gammadelta thymocyte development.
Eynon E, Livák F, Kuida K, Schatz D, Flavell R. Distinct effects of Jak3 signaling on alphabeta and gammadelta thymocyte development. The Journal Of Immunology 1999, 162: 1448-59. PMID: 9973401, DOI: 10.4049/jimmunol.162.3.1448.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell DivisionCell SurvivalGene ExpressionGene Rearrangement, delta-Chain T-Cell Antigen ReceptorGene Rearrangement, gamma-Chain T-Cell Antigen ReceptorGenes, bcl-2Janus Kinase 3MiceMice, Inbred C57BLMice, KnockoutMice, TransgenicProtein-Tyrosine KinasesReceptors, Antigen, T-Cell, alpha-betaReceptors, Antigen, T-Cell, gamma-deltaSignal TransductionT-Lymphocyte SubsetsConceptsJak3-/- miceGammadelta T cell lineagesThymocyte developmentTransduction of signalsTCRbeta chain gene rearrangementLineage differentiationGammadelta lineageCell lineagesGene resultsKinase 3Developmental blockadeEarly thymocyte differentiationCytokine receptorsGamma locusT-cell lineageTargeted deletionBcl-2 expressionThymocyte differentiationTCRbeta transgeneIL-2 familyLineagesDifferentiationImmature thymocytesTransgeneSevere reduction
1998
Alternative splicing of rearranged T cell receptor δ sequences to the constant region of the α locus
Livák F, Schatz D. Alternative splicing of rearranged T cell receptor δ sequences to the constant region of the α locus. Proceedings Of The National Academy Of Sciences Of The United States Of America 1998, 95: 5694-5699. PMID: 9576946, PMCID: PMC20441, DOI: 10.1073/pnas.95.10.5694.Peer-Reviewed Original ResearchConceptsCalpha geneTCRalpha/delta locusT cell receptor alpha/delta locusDelta locusAlpha/delta locusProtein coding capacityTranscriptional controlAlternative splicingSplicing variationsDistinct functional capacitiesAlternative transcriptsDelta proteinΑ locusChimeric proteinConstant genesAlpha proteinGene-deficient miceCoding capacityGenesThymocyte developmentAlphabeta thymocytesNovel insightsTCRbeta chainLociDistinct diversity